건강한 세포 만들어내는 운동 메카니즘 2022 NATURE..

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Molecular mechanisms of exercise contributing to tissue regeneration

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• Review Article
• Open access
• Published: 30 November 2022

Molecular mechanisms of exercise contributing to tissue regeneration

• Jibao Chen, 
• Ren Zhou, 
• Ye Feng & 
• Lin Cheng 

Signal Transduction and Targeted Therapy volume 7, Article number: 383 (2022) Cite this article

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Abstract

Physical activity has been known as an essential element to promote human health for centuries. Thus, exercise intervention is encouraged to battle against sedentary lifestyle. Recent rapid advances in molecular biotechnology have demonstrated that both endurance and resistance exercise training, two traditional types of exercise, trigger a series of physiological responses, unraveling the mechanisms of exercise regulating on the human body. Therefore, exercise has been expected as a candidate approach of alleviating a wide range of diseases, such as metabolic diseases, neurodegenerative disorders, tumors, and cardiovascular diseases. In particular, the capacity of exercise to promote tissue regeneration has attracted the attention of many researchers in recent decades. Since most adult human organs have a weak regenerative capacity, it is currently a key challenge in regenerative medicine to improve the efficiency of tissue regeneration. As research progresses, exercise-induced tissue regeneration seems to provide a novel approach for fighting against injury or senescence, establishing strong theoretical basis for more and more “exercise mimetics.” These drugs are acting as the pharmaceutical alternatives of those individuals who cannot experience the benefits of exercise. Here, we comprehensively provide a description of the benefits of exercise on tissue regeneration in diverse organs, mainly focusing on musculoskeletal system, cardiovascular system, and nervous system. We also discuss the underlying molecular mechanisms associated with the regenerative effects of exercise and emerging therapeutic exercise mimetics for regeneration, as well as the associated opportunities and challenges. We aim to describe an integrated perspective on the current advances of distinct physiological mechanisms associated with exercise-induced tissue regeneration on various organs and facilitate the development of drugs that mimics the benefits of exercise.

신체 활동은 

수세기 동안 인간의 건강을 증진하는 데 필수적인 요소로 알려져 왔습니다. 

따라서 

앉아서 생활하는 생활 방식에 맞서 싸우기 위해 

운동 개입이 권장됩니다. 

최근 분자 생명공학의 급속한 발전으로 

전통적인 두 가지 운동 유형인 지구력 및 저항 운동 훈련이 

일련의 생리적 반응을 유발하여 

인체에 대한 운동 조절 메커니즘을 밝혀내는 것으로 입증되었습니다. 

따라서 

운동은 

대사 질환, 신경 퇴행성 질환, 종양, 심혈관 질환 등 

다양한 질병을 완화하는 후보 접근법으로 기대되고 있습니다. 

특히 

운동이 조직 재생을 촉진하는 능력은 

최근 수십 년간 많은 연구자들의 관심을 끌었습니다. 

대부분의 성인 인체 장기는 

재생 능력이 약하기 때문에 

조직 재생의 효율성을 높이는 것이 

현재 재생 의학의 핵심 과제입니다. 

연구가 진행됨에 따라 운동으로 인한 조직 재생은 

부상이나 노화에 맞서 싸우는 새로운 접근 방식을 제공하여 점

점 더 많은 “운동 모방제”에 대한 강력한 이론적 근거를 확립하는 것으로 보입니다. 

이러한 약물은 

운동의 이점을 경험할 수 없는 사람들을 위한 의약품의 대안으로 작용하고 있습니다. 

여기에서는 

근골격계, 심혈관계, 신경계를 중심으로 

운동이 다양한 장기의 조직 재생에 미치는 이점에 대해 포괄적으로 설명합니다. 

또한 

운동의 재생 효과와 관련된 근본적인 분자 메커니즘과 

재생을 위한 새로운 치료 운동 모방체, 

그리고 관련 기회와 과제에 대해서도 논의합니다. 

우리는 

운동으로 인한 다양한 장기의 조직 재생과 관련된 

뚜렷한 생리적 메커니즘의 현재 발전에 대한 통합적인 관점을 설명하고 

운동의 이점을 모방하는 약물 개발을 촉진하는 것을 목표로 합니다.

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Introduction

Physical activity mainly refers to any bodily movement produced by skeletal muscles and results in energy expenditure, broadly encompassing exercise and sports, which have been done as part of daily living, occupation, leisure, and active transportation.1,2 Over the last few decades, physical activity has been convinced by clinical and experimental studies as an essential element of daily life and crucial to promote health and longevity.3,4,5 Importantly, it is reported that physical inactivity has become the fourth leading cause of death worldwide nowadays.6 According to 2020 World Health Organization (WHO) guidelines, it is stated that 150–300 min of moderate intensity, or 75–150 min of vigorous-intensity physical activity, or some equivalent combination of moderate intensity and vigorous-intensity aerobic physical activity should be undertaken per week.7 However, about one-third of adults worldwide do not meet the minimal intensity or time of physical activity recommended by WHO.8 Substantial evidence has shown that physical inactivity mostly has a negative impact on non-communicable diseases such as coronary heart disease,9 diabetes mellitus,10,11 cancer,12,13 and even mental health,14,15,16 dramatically aggravating the global health burden and shortening the life expectancy of people. Therefore, promotion of physical activity is one of the important methods to improve the quality of human lifespan.

Exercise is theoretically defined as a kind of planned, structured, and repetitive physical activity.1 As a kind of physical education activity and social cultural activity, regular exercise is accepted by more and more people. Basically, there are two types of exercise including endurance (aerobic) training and resistance (anaerobic) training (Fig. 1).17,18,19,20 Physiologically, endurance exercise training refers to the exercise in which glucose metabolism depends on oxygen under aerobic conditions, while resistance exercise training refers to the exercise in which weight or overload is carried out in anaerobic condition and it is a short period of high-intensity or maximal intensity activity.21,22,23 The former usually induces the adaptation of cardiovascular and respiratory systems, while the latter is more likely to result in muscle hypertrophy through increasing myofibrillar volume predominantly in type II fibers and it is accompanied by changes in central nervous system.24,25,26,27 According to the exercise testing and prescription guidelines of the American Academy of Sports Medicine,28 endurance exercise is a wide range of physical activities, such as walking, jogging, dancing, swimming and cycling, its intensity is lower than the maximum intensity and can last for several minutes to several hours.29 Endurance exercise training is based on the FITT (frequency, intensity, time, type)–VP (volume, progression) principle of exercise prescription, while the intensity of exercise can be described in terms of heart rate, oxygen consumption (VO2) and metabolic equivalent.2 Common resistance exercise training includes barbell bench press, barbell overhead squat, dumbbell bicep curl and other strength exercises. The optimal training load for strength training is still being explored.30 It is suggested that performing a single set of 6–12 repetitions with loads ranging from approximately 70–85% one repetition maximum 2–3 times per week may produce sufficient training effect.31 Indeed, the complexity of physical activities makes no such clear boundary between the two types of exercise, as endurance exercise may become anaerobic if the intensity of aerobic exercise exceeds the anaerobic threshold. With a better understanding of the physiological responses triggered by different types of exercise, a variety of exercise strategies have emerged, including high-intensity interval training (HIIT) and moderate-intensity continuous exercise training (MICT). Notably, HIIT is getting more popular among the fitness enthusiasts and athletes because it has demonstrated superiority in cardiorespiratory fitness,32,33,34 weight loss,35,36 and improvement of chronic diseases.37 Overall, the diversity of exercise triggers different physiological adaptations, allowing for the targeted utilization of exercise training to make improvements of the various physical states.

소개

신체 활동은

주로 골격근에 의해 생성되고 에너지 소비를 초래하는 모든 신체 움직임을 말하며,

일상생활, 직업, 여가, 활동적인 교통수단의 일부로 수행되는

운동과 스포츠를 광범위하게 포함합니다.1,2

지난 수십 년 동안 신체 활동은

임상 및 실험 연구를 통해 일상 생활의 필수 요소이자 건강과 장수를 증진하는 데 중요한 요소로 확신되었습니다.3,4,5

중요한 것은

오늘날 신체 비활동이

전 세계적으로 네 번째로 주요 사망 원인이 되었다는 보고가 있습니다.6

2020년 세계보건기구(WHO) 가이드라인에 따르면,

일주일에 150-300분 중강도 신체 활동 또는

75-150분 격렬한 강도의 신체 활동 또는 중강도 및 격렬한 강도의 유산소 신체 활동의

동등한 조합을 수행해야 한다고 명시되어 있습니다.7

그러나

전 세계 성인의 약 1/3은

WHO가 권장하는 최소한의 신체 활동 강도나 시간을 충족하지 못하고 있습니다.8

신체 활동 부족은

관상동맥 심장 질환,9 당뇨병,10,11 암,12,13 심지어 정신 건강,14,15,16 과 같은

비전염성 질환에 부정적인 영향을 미치고

전 세계 건강 부담을 극적으로 악화시키고

사람들의 기대 수명을 단축시킨다는 상당한 증거가 있습니다.

따라서

신체 활동의 증진은

인간의 삶의 질을 향상시키는 중요한 방법 중 하나입니다.

운동은

이론적으로 계획적이고 구조적이며 반복적인 신체 활동의 일종으로 정의됩니다.1

체육 활동 및 사회 문화 활동의 일종으로서 규칙적인 운동은 점점 더 많은 사람들에게 받아들여지고 있습니다. 기본적으로 운동에는 지구력(유산소) 훈련과 저항력(무산소) 훈련의 두 가지 유형이 있습니다(그림 1).17,18,19,20 생리적으로 지구력 운동 훈련은 유산소 조건에서 산소에 의존하여 포도당 대사를 하는 운동을 말하며, 저항력 운동 훈련은 무산소 조건에서 체중 또는 과부하를 가하는 운동으로 단기간 고강도 또는 최대 강도 활동을 하는 것을 말합니다.21,22,23

전자는 일반적으로 심혈관계와 호흡계의 적응을 유도하는 반면, 후자는 주로 제2형 섬유를 중심으로 근섬유 부피 증가를 통한 근육 비대를 초래할 가능성이 높고 중추신경계의 변화를 동반한다.24,25,26,27

미국 스포츠 의학 아카데미의 운동 테스트 및 처방 지침에 따르면,28 지구력 운동은 걷기, 조깅, 춤, 수영 및 자전거 타기와 같은 광범위한 신체 활동으로, 강도는 최대 강도보다 낮으며 몇 분에서 몇 시간 동안 지속될 수 있습니다.29 지구력 운동 훈련은 운동 처방의 FITT(빈도, 강도, 시간, 유형)-VP(볼륨, 진행) 원칙에 기반하며, 운동 강도는 심박수, 산소 소비량(VO2) 및 대사량으로 설명할 수 있습니다.2 일반적인 저항 운동 훈련에는 바벨 벤치 프레스, 바벨 오버헤드 스쿼트, 덤벨 바이셉 컬 및 기타 근력 운동이 포함됩니다. 근력 운동을 위한 최적의 훈련 부하는 아직 연구 중입니다.30 주 2~3회 최대 약 70~85%의 부하로 6~12회씩 한 세트를 반복하면 충분한 훈련 효과를 얻을 수 있다고 합니다.31

실제로 신체 활동의 복잡성으로 인해 유산소 운동의 강도가 무산소 역치를 초과하면 지구력 운동이 무산소가 될 수 있으므로 두 운동 유형 사이에 명확한 경계가 존재하지 않습니다. 다양한 유형의 운동이 유발하는 생리적 반응에 대한 이해가 높아지면서 고강도 인터벌 트레이닝(HIIT)과 중강도 연속 운동 트레이닝(MICT)을 비롯한 다양한 운동 전략이 등장했습니다. 특히 HIIT는 심폐 건강,32,33,34 체중 감량,35,36 및 만성 질환 개선에 탁월한 효과가 입증되어 피트니스 애호가와 운동선수들 사이에서 인기를 얻고 있습니다.37 전반적으로 운동의 다양성은 다양한 생리적 적응을 유발하여 다양한 신체 상태를 개선하기 위해 운동 훈련을 표적으로 활용할 수 있게 해줍니다.

Fig. 1

Benefits of exercise-induced tissue regeneration. a Exercise induces physiological hypertrophy of left ventricle and reduction of myocardial infarction area by promoting the proliferation of cardiomyocytes. b Exercise induces muscle hypertrophy by promoting the proliferation of the satellite cells in both physiological and pathological conditions. Angiogenesis and mitochondrial biosynthesis are helpful in delaying muscle fatigue. c Exercise enhances hippocampal neurogenesis, myelin regeneration, axon regeneration, and cerebral angiogenesis to improve the motor, sensory, and cognitive functions. Exercise can also improve the sensory and motor functions after spinal cord injury and promote survival and differentiation of transplanted stem cells. d Exercise increases the branches of nerve fibers in the proximal skin, and promotes axon cross-sectional area (CSA), myelin sheath thickness, Schwann cell’s nucleus area and neurogenesis, so as to relieve the pain, improving sensation and motor function of patients with peripheral neuropathy. e Exercise can change the bone marrow microenvironment, promote the proliferation of hematopoietic stem and progenitor cells and the production of leukocytes. f Exercise regulates skeletal stem cell to differentiate into osteoblasts and chondrocytes, as well as bone angiogenesis, increasing bone mineral density (BMD). Besides, exercise induces the regeneration of post-traumatic cartilage lesions. Exercise is also considered as an effective adjuvant to stem cell-based therapy and the application of biomaterials or devices for cartilage regeneration. g Exercise promotes the regeneration ability of fatty liver, improving its tolerance to ischemia. Besides, exercise can restore liver function by promoting hepatocyte proliferation and mitochondrial biosynthesis in patients with partial hepatectomy. Created with BioRender

운동으로 인한 조직 재생의 이점

a 운동은 심근 세포의 증식을 촉진하여 좌심실의 생리적 비대와 심근 경색 면적 감소를 유도합니다.

b 운동은 생리적 및 병리학 적 조건 모두에서 위성 세포의 증식을 촉진하여 근육 비대를 유도합니다. 혈관 신생과 미토콘드리아 생합성은 근육 피로를 지연시키는 데 도움이 됩니다.

c 운동은 해마 신경 생성, 미엘린 재생, 축삭 재생 및 뇌 혈관 생성을 강화하여 운동, 감각 및 인지 기능을 향상시킵니다. 운동은 또한 척수 손상 후 감각 및 운동 기능을 개선하고 이식 된 줄기 세포의 생존과 분화를 촉진 할 수 있습니다.

d 운동은 근위 피부의 신경 섬유 가지를 증가시키고 축삭 단면적 (CSA), 수초 두께, 슈반 세포의 핵 면적 및 신경 발생을 촉진하여 말초 신경 병증 환자의 통증을 완화하고 감각 및 운동 기능을 개선합니다.

e 운동은 골수 미세 환경을 변화시키고 조혈 줄기 및 전구 세포의 증식과 백혈구 생성을 촉진 할 수 있습니다.

f 운동은 골격 줄기 세포가 조골 세포와 연골 세포로 분화하도록 조절하고 뼈 혈관 신생을 조절하여 골밀도 (BMD)를 증가시킵니다. 또한 운동은 외상 후 연골 병변의 재생을 유도합니다. 운동은 또한 줄기세포 기반 치료와 연골 재생을 위한 생체 재료 또는 장치의 적용에 효과적인 보조제로 간주됩니다.

g 운동은 지방간의 재생 능력을 촉진하여 허혈에 대한 내성을 개선합니다. 또한 운동은 부분 간 절제술을 받은 환자의 간세포 증식과 미토콘드리아 생합성을 촉진하여 간 기능을 회복시킬 수 있습니다.

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Over the past centuries, exercise training has been regarded as an effective approach to enhance tissue function under normal physiological condition and restore function under diverse pathological conditions, including cardiovascular diseases,38,39,40 chronic metabolic syndromes,41,42 neurological and psychiatric disorders,43,44,45 and cancer,19,46,47,48 which are mainly treated by chemical drugs. However, many diseases with loss of functional cells rely on cell supplement for tissue or organ regeneration. Nowadays, the definition of regeneration has been getting more precise and clearer, known as embryonic regulation, homeostatic regeneration, and restorative regeneration, respectively.49,50 As restorative regeneration stands for the ultimate goal that implantation of regenerated tissue constructs into the body to repair injuries or replace the physiological function, it makes great sense to find out how homeostatic tissues initiate the regeneration program by triggering a coherent immune response, appropriate cell plasticity, as well as stem and stromal cell responses following injury.51 As is well known, the basic process of tissue or organ regeneration should involve various forms of cellular plasticity first, which means that regeneration of tissues damaged by various injury modify tissue architecture through coordinated cell proliferation, differentiation, and apoptosis.52 Regeneration physiologically contributes to homeostasis against cell apoptosis, but it shows so limited ability to repair ischemic or impaired tissue for fully functional recovery in several vital organs, for instance cardiovascular and nervous system.53,54,55,56 Therefore, many approaches are currently applied to tissue regeneration therapy, including activation of endogenous stem cells and supplement with exogenous stem cells.57,58,59,60 Importantly, it has been suggested in recent decades that exercise is also able to contribute to promoting the restoration of damaged tissues, which provides a novel theoretical basis for tissue regeneration.

Since research on restorative regeneration has attracted more and more attention, exercise-induced tissue regeneration provides new therapeutic strategies. Recently it has been reported that only high-intensity training can stimulate changes in markers of mitochondrial respiratory function in skeletal muscle and enhance oxidative phosphorylation levels,61 which proves that there is a dose-dependent response to exercise duration and/or intensity again.3 However, not all individuals are able to achieve the level of exercise needed to experience the wide range of health benefits that exercise provides. Thus, it has been one of the most fascinating topics how exercise affects various organs and promotes injury repair, which drives researchers to mimic these effects with pharmaceuticals. To develop effective therapeutic approaches, it is crucial to understand the underlying mechanisms of the regenerative effects triggered by exercise, at the level of molecules, cells, and systems. This review will summarize recent advances in the benefits of exercise on different vital organs, thereby revealing the underlying molecular mechanisms and the potential mimetics from the perspective of exercise-induced tissue regeneration for further research and clinical applications.

지난 수세기 동안 운동 훈련은 심혈관 질환,38,39,40 만성 대사 증후군,41,42 신경 및 정신 장애,43,44,45 및 암,19,46,47,48 등 주로 화학 약물로 치료하는 다양한 병리학적인 조건에서 정상적인 생리 상태에서 조직 기능을 향상하고 기능을 회복하는 효과적인 접근법으로 여겨져 왔습니다. 그러나 기능 세포가 손실된 많은 질병은 조직이나 장기 재생을 위해 세포 보충제에 의존합니다. 오늘날 재생의 정의는 각각 배아 조절, 항상성 재생, 회복 재생으로 알려져 더욱 정확하고 명확해지고 있습니다.49,50 회복 재생은 재생된 조직을 체내에 이식하여 손상을 복구하거나 생리적 기능을 대체하는 궁극적인 목표를 의미하므로, 항상성 조직이 손상 후 일관된 면역 반응, 적절한 세포 가소성, 줄기세포 및 간질세포 반응을 유발하여 재생 프로그램을 시작하는 방법을 찾는 것이 큰 의미가 있습니다.51

잘 알려진 바와 같이 조직 또는 장기 재생의 기본 과정은

다양한 형태의 세포 가소성을 먼저 포함해야 하며,

이는 다양한 손상으로 손상된 조직의 재생이 조정된 세포 증식, 분화 및 세포 사멸을 통해

조직 구조를 수정한다는 것을 의미합니다.52

재생은 생리적으로 세포 사멸에 대한 항상성에 기여하지만,

심혈관 및 신경계와 같은 여러 중요한 기관에서 허혈성 또는 손상된 조직을 복구하여 완전한 기능을 회복하는 데는 매우 제한적인 능력을 보입니다.53,54,55,56 따라서 현재 조직 재생 치료에는 내인성 줄기세포 활성화, 외인성 줄기세포 보충 등 많은 접근법이 적용되고 있습니다.57,58,59,60 중요한 것은 최근 수십 년간 운동도 손상된 조직의 회복 촉진에 기여할 수 있다는 것이 제시되면서 조직 재생의 새로운 이론적 기반을 제공한다는 점입니다.

회복 재생에 대한 연구가 점점 더 많은 관심을 끌면서 운동으로 인한 조직 재생은 새로운 치료 전략을 제공합니다.

최근에는

고강도 훈련만이 골격근의 미토콘드리아 호흡 기능 마커의 변화를 자극하고

산화적 인산화 수준을 향상시킬 수 있다는 보고가 있었으며,61

이는 운동 기간 및/또는 강도에 대한 용량 의존적 반응이 다시 있다는 것을 증명합니다.3

그러나 모든 개인이 운동이 제공하는 광범위한 건강상의 이점을 경험하는 데 필요한 수준의 운동에 도달할 수 있는 것은 아닙니다. 따라서 운동이 다양한 장기에 어떤 영향을 미치고 부상 회복을 촉진하는지는 가장 흥미로운 주제 중 하나이며, 연구자들은 이러한 효과를 의약품으로 모방하기 위해 노력하고 있습니다. 효과적인 치료법을 개발하려면 분자, 세포, 시스템 수준에서 운동으로 촉발되는 재생 효과의 근본적인 메커니즘을 이해하는 것이 중요합니다. 이 리뷰에서는 운동이 다양한 주요 장기에 미치는 영향에 대한 최근의 연구 성과를 요약하여 운동으로 인한 조직 재생의 관점에서 근본적인 분자 메커니즘과 잠재적인 모방 물질을 밝혀 추가 연구 및 임상 적용을 위한 기초를 마련하고자 합니다.

Benefits of exercise on tissue regeneration

Exercise-induced muscle regeneration

The musculoskeletal system is an integral component of mobility and strength in the human body. Skeletal muscles, as the most important component of the musculoskeletal system, are characterized by myofibers and connective tissue, making up more than 35% of the adult body and containing 50–75% of all body proteins.62 The mechanical injury, ischemia injury, inflammatory injury and even congenital or acquired atrophy are described as those that involve disrupted connective tissues, leading to loss of skeletal muscle mass, reduced motor unit discharge rate, and impaired function.63 It has been uncovered that moderate exercise training enhances muscle regeneration after injury, as skeletal muscle mass recovery after extensive injury can be improved by contractile activity. In general, it has been widely convinced that the local adaptations of endurance exercise in skeletal muscle mostly focus on increased mitochondrial biogenesis and capillary density, which aids in the body’s ability to transport and use oxygen to generate energy and therefore delay the onset of muscle fatigue during prolonged aerobic performance.64 However, it has been also shown that endurance exercise training promotes maintenance of muscle mass and recovery after injury.65,66 While in rat models of notexin-induced soleus muscle degeneration, running exercise ensured the full recovery of muscle mass and muscle cross-sectional area during muscle regeneration, and made muscle recovery much faster than sedentary group.67,68 In contrast, resistance exercise training is more conducive to an increase in muscle strength and power as a result of neuromuscular adaptations, increases in muscle cross-sectional area (CSA), and alterations in connective tissue stiffness.69 Strength training significantly improved protracted quadriceps muscle atrophy in anterior cruciate ligament reconstruction patients via increasing muscle fibers CSA and type I fibers.70 Of note, it has been reported that HIIT, the novel combination exercise training strategy, promotes muscle regeneration, innervation, and vascularization in regenerated areas of volumetric muscle loss injury, even enhancing the healing effect of stem cell transplantation with an amniotic membrane scaffold.71 As mentioned about muscle regeneration induced by various exercise training, further studies should seek to assess different loads/modes (uphill vs. flat) with the same volume to confirm‎ whether this affects muscle regeneration following training and provide compound exercise patterns to improve the efficiency of muscle regeneration.

Myogenesis follows after early inflammation and revascularization, and later fibrosis and re-innervation, resulting restoration of muscle mass and function.72 The bona fide tissue-specific stem cell, considered as a key component in myogenesis, in human adult skeletal muscle is the satellite cell.73,74 It has been convinced that the satellite cells are activated, proliferating, and differentiating after muscle fibers get injured, whose mitotic activity can be enhanced by exercise in the forms of endurance or resistance exercise training.75,76 In addition, skeletal muscle regeneration by the modulation of satellite cells is affected by the balance between pro- and anti-inflammatory macrophages.77 Exercise has been confirmed to cause the transition from the M1 to M2 macrophage phenotype, regulating the satellite cells proliferation and differentiation in the injury sites.78,79,80 Moreover, fibro-adipogenic progenitors (FAPs) has also been confirmed to get activated in response to muscle injury and establish functional interactions with the inflammatory cells and the satellite cells to promote muscle repair.81,82,83 More recently, it has been demonstrated that exercise increases and activates satellite cells by promoting FAPs senescence in the mouse models of acute muscle injury and chronic inflammatory myopathy, which provides a new therapeutic strategy for exercise-induced muscle regeneration (Fig. 1b).84

운동이 조직 재생에 미치는 이점

운동으로 인한 근육 재생

근골격계는 인체의 이동성과 근력을 구성하는 필수적인 요소입니다. 근골격계의 가장 중요한 구성 요소인 골격근은 근섬유와 결합 조직으로 이루어져 있으며, 성인 신체의 35% 이상을 구성하고 전체 신체 단백질의 50~75%를 함유하는 것이 특징입니다.62 기계적 손상, 허혈 손상, 염증성 손상, 선천적 또는 후천적 위축은 결합 조직이 파괴되어 골격근량의 손실, 운동 단위 방전율 감소 및 기능 장애로 이어지는 것으로 설명됩니다.63 광범위한 손상 후 골격근량 회복은 수축 활동에 의해 개선될 수 있으므로 적당한 운동 훈련은 손상 후 근육 재생을 향상시킨다는 사실이 밝혀졌습니다. 일반적으로 골격근에서 지구력 운동의 국소적 적응은 주로 미토콘드리아 생성과 모세혈관 밀도 증가에 초점을 맞추며, 이는 신체의 산소 운반 및 사용 능력을 도와 에너지를 생성하여 장시간 유산소 운동 수행 중 근육 피로의 시작을 지연시킵니다.64 그러나 지구력 운동 훈련이 근육량 유지와 부상 후 회복을 촉진한다는 사실도 밝혀졌습니다.65,66 노텍신으로 유도된 가자미근 변성의 쥐 모델에서 달리기 운동은 근육 재생 동안 근육량과 근육 단면적의 완전한 회복을 보장하고 앉아있는 그룹보다 근육 회복을 훨씬 빠르게 만들었습니다.67,68 반대로 저항 운동 훈련은 신경근 적응, 근육 단면적(CSA) 증가, 결합 조직 강성의 변화로 인한 근력과 힘의 증가에 더 도움이 됩니다.69 근력 운동은 근섬유 CSA와 제1형 섬유의 증가를 통해 전방십자인대 재건 환자의 장기적인 대퇴사두근 위축을 유의하게 개선했습니다.70 특히, 새로운 복합 운동 훈련 전략인 HIIT는 체적 근육 손실 손상 부위의 근육 재생, 신경 및 혈관 재생을 촉진하고 심지어 양막 스캐폴드를 사용한 줄기세포 이식의 치유 효과를 향상시킨다는 보고가 있습니다.71 다양한 운동 훈련에 의한 근육 재생에 대해 언급했듯이, 추가 연구에서는 동일한 부피로 다양한 부하/모드(오르막과 평지)를 평가하여 훈련 후 근육 재생에 영향을 미치는지 확인하고 근육 재생의 효율성을 높이기 위한 복합적인 운동 패턴을 제공해야 합니다.

근육은 초기 염증과 혈관 재생, 이후 섬유화와 재신경화 과정을 거쳐 근육량과 기능이 회복됩니다.72 인간 성인 골격근에서 근육 형성의 핵심 구성 요소로 간주되는 조직 특이적 줄기세포는 위성 세포입니다.73,74 위성 세포는 근섬유가 손상된 후 활성화, 증식 및 분화되며, 지구력 또는 저항 운동 훈련 형태의 운동에 의해 유사 분열 활동이 향상 될 수 있다고 확신되었습니다 .75,76 또한 위성 세포의 조절에 의한 골격근 재생은 친 염증 대 식세포와 항 염증 대 식세포 사이의 균형에 의해 영향을받습니다 .77 운동은 손상 부위에서 위성세포의 증식과 분화를 조절하여 M1에서 M2 대식세포 표현형으로 전환시키는 것으로 확인되었습니다.78,79,80 또한, 근육손상에 반응하여 섬유-지방전구세포(FAP)가 활성화되고 염증세포 및 위성세포와 기능적 상호작용을 하여 근육 회복을 촉진하는 것으로 확인되었습니다.81,82,83 최근에는 운동이 급성 근육 손상 및 만성 염증성 근병증 마우스 모델에서 FAP의 노화를 촉진하여 위성 세포를 증가시키고 활성화하여 운동 유발 근육 재생을위한 새로운 치료 전략을 제공한다는 것이 입증되었습니다 (그림 1b).84

Exercise-induced bone and cartilage regeneration

Briefly, the primary features of an ageing skeleton are loss of bone, degraded articular cartilage, and degenerate, narrowed intervertebral discs, contributing to pain and loss of mobility. Physical activity has long been recognized as an essential factor in the maintenance of skeletal health. An abundance of studies has shown that both endurance and resistance exercise physiologically promote bone growth of teenagers and increase peak bone mass, which contributes to prevention of osteoporosis in adult stages.85,86 Thus, it is convinced that the common decline in bone mass during ageing attenuates, by following specific exercise programs, especially in postmenopausal women.87 Although endurance exercise is important in maintaining overall health, the resistance training may be more applicable to the basic rules of bone adaptation and site-specific effects of exercise.88 Recently an 8-week of exercise protocol of resistance exercise or endurance exercise experiment confirmed resistance exercise, but not endurance exercise, is likely to be effective in increasing bone strength.89 Indeed, it has been confirmed that bone responds more positively to mechanical loads that induce high-magnitude strains at high rates or frequencies, such as quick jumping, which causes the weakness of exercise’s ability to evoke osteogenesis in traditional training patterns.90 Thus, Davison et al.91 established a novel exercise equipment and exercise training patterns to improve the efficiency of osteogenesis, giving hope to those afflicted with bone loss (osteoporosis, or osteopenia) conditions. In addition, bone regeneration also relies on vascularization of the ossifying tissue, called angiogenesis-osteogenesis coupling.92 Yao et al.93 found that treadmill running could physiologically increase vessel number in the proximal metaphysis of rats, and significant changes of bone mineral density (BMD) in response to exercise. Subsequently, a set of researches have clarified that exercise stimulates angiogenesis during bone defect healing, accelerating bone regeneration as well.94,95

Chondral injury is a pathology with high preval‎ence, reaching as much as 63% of general population and 36% among athletes.96,97 Despite inappropriate or excessive exercise primarily aggravates joint damage, moderate exercise is recognized to exert a beneficial effect on the healing of osteoarthritis. It has been widely reported that both traditional training, such as running and swimming, and non-traditional training, such as pilates and yoga, are effective in the management of knee and hip osteoarthritis, mainly regarding pain and strength improvement.98,99,100 Notably, rodent models have shown that moderate exercise prevents the progression of post-traumatic cartilage lesions.101,102 Additionally, it is suggested that there is a dose–response relationship between loading and intervertebral disc regenerative processes, implying that the loading pattern typically used in the lumbar extension resistance exercise interventions (high load, low volume, and low frequency) may impart the regeneration of the intervertebral discs.103 Actually, cartilage tissue presents limited cellularity and lacks a vascular system, leading to restrained healing capability, which brings more attention to the implantation on promoting regeneration, including stem cell transplantation and the application of biomaterials or devices.104,105,106 Importantly, exercise is also considered as an effective adjuvant to cartilage regeneration therapy. Substantial evidence has shown that exercise enhances the potential of autologous chondrocyte implants, matrix-induced autologous chondrocyte implants, and mesenchymal stem cell (MSC) implants for the successful treatment of damaged articular cartilage and subchondral bone by downregulating osteoclastogenic cytokine production and upregulating antiosteoclastogenic cytokine production by circulating immune cells.107 More recently, Liu et al.108 demonstrated exercise promoted hyalinecartilage regeneration and completely healed cartilage in osteochondral defect rabbits with a biodegradable piezoelectric scaffold implanted, which is potentially applicable to the treatment of osteoarthritis.

As is well known, physical activities induce mechanical stress to the joints and bones, promoting stem cell proliferation and differentiation in the process of regeneration.103,109,110,111 It has been reported that acute exercise increases circulating stem and progenitor cells, including hematopoietic stem cells (HSCs) and MSCs.112 Interestingly, osteoblasts and chondrocytes are derived from multipotent skeletal stem cells of MSCs,113,114 while osteoclasts are derived from the macrophage lineage of HSCs.115 Bone formation is carried out by osteoblasts and resorption is carried out by osteoclasts, which means that bone regeneration relies on the balance of two types of cells. Exercise has been shown to induce skeletal stem cells to differentiate towards osteoblasts. It is found that endurance training increases the total number of bone marrow MSCs in mice, enhances the osteogenic differentiation potential of MSCs, and inhibits the adipogenic potential of MSCs.116 Of note, osteoclast recruitment to the future resorption sites is mainly controlled by osteoblasts. It has been shown that moderate exercise increases the expression‎ of osteoprotegerin and decreases the expression‎ of receptor activator of nuclear factor κB ligand, both of which are expressed by osteoblasts, inhibiting osteoclast differentiation and activity.117,118,119 Thus, the regulatory mechanisms of stem cells responding to mechanical stimuli and biochemical signaling is critical for exercise-induced bone regeneration (Fig. 1f).

운동으로 인한 뼈와 연골 재생

간단히 말해, 노화된 골격의 주요 특징은 뼈의 손실, 관절 연골의 퇴화, 추간판의 퇴행 및 좁아짐으로 인한 통증과 이동성 상실입니다. 신체 활동은 골격 건강을 유지하는 데 필수적인 요소로 오랫동안 인식되어 왔습니다. 많은 연구에 따르면 지구력 운동과 저항 운동 모두 생리적으로 청소년의 뼈 성장을 촉진하고 최대 골량을 증가시켜 성인기 골다공증 예방에 기여합니다.85,86 따라서 특히 폐경 후 여성에서 특정 운동 프로그램을 따르면 노화에 따른 일반적인 골량 감소가 약화되는 것으로 확신됩니다.87 지구력 운동은 전반적인 건강 유지에 중요하지만, 저항 운동은 뼈 적응의 기본 규칙과 운동의 부위별 효과에 더 적용될 수 있습니다.88 최근 저항 운동 또는 지구력 운동의 8주 운동 프로토콜 실험에서 지구력 운동이 아닌 저항 운동이 골강도를 높이는 데 효과적 일 가능성이 있음을 확인했습니다.89 실제로 뼈는 빠른 점프와 같이 높은 속도 또는 빈도로 높은 크기의 변형을 유도하는 기계적 부하에 더 긍정적으로 반응하여 전통적인 훈련 패턴에서 운동이 골 형성을 유발하는 능력이 약화되는 것으로 확인되었습니다.90 따라서 데이비슨 외.91은 골 형성의 효율성을 개선하기 위해 새로운 운동 장비와 운동 훈련 패턴을 확립하여 골 손실(골다공증 또는 골감소증) 질환을 앓고 있는 사람들에게 희망을 주었습니다. 또한 뼈 재생은 혈관 신생-골 형성 결합이라고 하는 골화 조직의 혈관 생성에도 의존합니다.92 Yao 등.93은 러닝머신 달리기가 생리적으로 쥐의 근위부 형이상학에서 혈관 수를 증가시키고 운동에 반응하여 골밀도(BMD)의 상당한 변화를 일으킬 수 있다는 사실을 발견했습니다. 그 후 일련의 연구를 통해 운동이 뼈 결손 치유 과정에서 혈관 생성을 자극하여 뼈 재생도 촉진한다는 사실이 밝혀졌습니다.94,95

연골 손상은 일반 인구의 63%, 운동 선수의 36%에 달할 정도로 유병률이 높은 병리입니다.96,97 부적절하거나 과도한 운동은 주로 관절 손상을 악화시키지만, 적당한 운동은 골관절염 치유에 유익한 효과를 발휘하는 것으로 인식되고 있습니다. 달리기, 수영과 같은 전통적인 운동과 필라테스, 요가와 같은 비 전통적인 운동 모두 무릎 및 고관절 골관절염 관리에 효과적이며, 주로 통증과 근력 향상에 효과가 있다고 널리 보고되고 있습니다.98,99,100 특히 설치류 모델에서는 적당한 운동이 외상 후 연골 병변의 진행을 예방하는 것으로 나타났습니다.101,102 또한, 부하와 추간판 재생 과정 사이에는 용량 반응 관계가 있는 것으로 제안되는데, 이는 요추 신전 저항 운동 중재에 일반적으로 사용되는 부하 패턴(고부하, 저용량, 저주파)이 추간판 재생에 영향을 줄 수 있음을 암시합니다.103 실제로 연골 조직은 세포가 제한적이고 혈관계가 부족하여 치유 능력이 제한적이기 때문에 줄기세포 이식, 생체 재료 또는 장치 적용 등 재생 촉진에 대한 관심이 높아지고 있습니다.104,105,106 중요한 것은 운동도 연골 재생 치료의 효과적인 보조제로 간주된다는 점입니다. 운동이 파골세포 생성 사이토카인 생성을 하향 조절하고 순환 면역 세포에 의한 항파골세포 생성 사이토카인 생성을 상향 조절함으로써 자가 연골세포 이식, 매트릭스 유도 자가 연골세포 이식, 중간엽 줄기세포(MSC) 이식술의 잠재력을 높여 손상된 관절 연골과 연골하 뼈를 성공적으로 치료할 수 있다는 상당한 증거가 밝혀졌습니다.107 최근에 Liu 등.108은 생분해성 압전 스캐폴드를 이식한 골연골 결손 토끼에서 운동이 히알린 연골 재생을 촉진하고 연골을 완전히 치유하여 골관절염 치료에 잠재적으로 적용될 수 있음을 입증했습니다.

잘 알려진 바와 같이 신체 활동은 관절과 뼈에 기계적 스트레스를 유발하여 재생 과정에서 줄기세포의 증식과 분화를 촉진합니다.103,109,110,111 급성 운동은 조혈 줄기세포(HSC)와 중간엽 줄기세포(MSC)를 포함한 순환 줄기세포와 전구세포를 증가시키는 것으로 보고되었습니다.112 흥미롭게도 조골세포와 연골세포는 조골세포의 다능성 골격 줄기세포에서 유래하며,113,114 파골세포는 HSC의 대식세포 계통에서 유래합니다.115 뼈 형성은 조골세포가 수행하고 재흡수는 파골세포가 수행하므로 뼈 재생은 두 유형의 세포의 균형에 의존한다는 것을 의미합니다. 운동은 골격 줄기 세포가 조골 세포로 분화하도록 유도하는 것으로 나타났습니다. 지구력 훈련은 생쥐의 골수 중간엽 줄기세포의 총 수를 증가시키고, 중간엽 줄기세포의 골 형성 분화 잠재력을 향상시키며, 중간엽 줄기세포의 지방 형성 잠재력을 억제하는 것으로 밝혀졌습니다.116 특히, 향후 흡수 부위로의 파골세포 모집은 주로 조골세포에 의해 조절된다는 점에 주목할 필요가 있습니다. 적당한 운동은 오스테오프로테제린의 발현을 증가시키고 파골세포에서 발현되는 핵인자 κB 리간드의 수용체 활성화제의 발현을 감소시켜 파골세포 분화와 활동을 억제하는 것으로 나타났습니다.117,118,119 따라서 기계적 자극과 생화학적 신호에 반응하는 줄기세포의 조절 메커니즘은 운동으로 인한 뼈 재생에 중요합니다 (그림 1f).

Exercise-induced cardiac regeneration

The benefits of exercise on cardiovascular system have been extensively reported.38,120,121 It is widely accepted that both endurance and resistance exercise training contribute to larger left ventricle structures than sedentary controls from the imaging findings, presenting physiological cardiac hypertrophy.122 Thus, one of the most significant exercise-induced adaptations has been described as promoting cardiac growth. However, it has been discovered that the renewal of cardiomyocytes gradually decreases from 1% turning over annually at the age of 20 to 0.3% at the age of 75, implying that adult human cardiomyocytes has a limited self-renewing capacity.53 Importantly, Boström et al.123 demonstrated that adult cardiomyocytes physiologically increased in both size and proliferation rate in response to exercise in mouse models. Meanwhile, it has been identified that endurance exercise increases birth of new cardiomyocytes in adult mice (~4.6-fold) based on incorporation of 15N-thymidine by multi-isotope imaging mass spectrometry.124 Therefore, exercise training provides a new intervention for enhancing the proliferation of cardiomyocytes.

Interestingly, Bei et al.125 stated that cardiomyocyte proliferation was not necessary for exercise-induced cardiac growth but required for its protection against ischemic injury. Ischemic injury, a mismatch of oxygen and substrate supply and demand in the myocardium, is one of the most predominant causes of cardiomyocyte loss. Exercise has been found to reduce adverse ventricular remodeling and cardiac dysfunction when initiated after infarction in animal models126,127 and humans128 for decades. Furthermore, it was found that myocardial infarct size significantly decreased in ischemia injury rats at least 1 week following the cessation of 5 consecutive days HIIT training, implying the sustained capability of exercise in cardiac repair.129 Subsequently, a range of studies have found that exercise increases numerous circulating factors to promote cardiomyocyte proliferation and reverse pathological cardiac remodeling in post-infarction models.130,131,132,133,134 Importantly, Vujic et al.124 demonstrated that exercise induced a robust cardiomyogenic response in an extended border zone of the infarcted area, validating the endogenous cardiomyocyte generation induced by exercise in the process of myocardial injury repair. However, previous studies have been done in the acute phase of cardiomyocyte loss, the effect of exercise on the pathological state of the chronic phase deserves further investigation.

Although exercise has protected against pathological cardiac remodeling, the effect of myocardial restoration after ischemic injury appears to vary from different exercise types.135,136 Interestingly, it has been found that HIIT, the popular exercise strategy, is not superior to MICT in changing left ventricular remodeling or aerobic capacity in the heart failure patients with preserved ejection fraction137 or reduced ejection fraction.138 Additionally, recently it has been reported that moderate heart rate reduction induces cardiomyocytes proliferation under physiological conditions and promotes cardiac regenerative repair after myocardial injury by inducing G1/S transition and increasing the expression‎ of glycolytic enzymes in cardiomyocytes, which is exactly the opposite of the exercise-induced rapid heart rate.139 Thus, the mechanism of exercise-induced myocardial regeneration is quite complex, the effects of different training patterns and training intensities in cardiac regeneration needs further exploration. It is rational to investigate exercise mimetics to balance the benefits and drawbacks of exercise. Furthermore, there are other causes of myocardial injury, such as hypertension140 and cancer,141 leading to cardiomyocyte death, whether exercise training counteracts induced-cell death by promoting cardiomyocyte proliferation also remains unknown (Fig. 1a).

Exercise-induced regeneration in central nervous system

Neural stem and progenitor cells (NSPCs) are major promoters of central nervous system (CNS) regeneration, which migrate and differentiate into highly specified networks of neurons via neurogenesis, while oligodendrocytes and astrocytes are generated via gliogenesis.142 NSPCs response to CNS injury is extraordinarily complex and dependent upon the extent and location of injury, thus the endogenous adult neurogenesis has been highly controversial. Recently, it has been confirmed that the hippocampus contains NSPCs that continue to generate new neurons, called adult hippocampal neurogenesis (AHN), which almost continues across the lifespan, though declining with aging.143,144 

Age-related neurodegenerative diseases are probably associated with impaired AHN. These animal studies have shown that voluntary exercise promotes hippocampal neurogenesis and prevents age-related decline in cell-proliferation in this brain structure.145,146 Furthermore, it has also been revealed that exercise induces volumetric retention in the left hippocampus in humans, implying endurance exercise interventions are useful for preventing age-related hippocampal deterioration.147 Besides aging, trauma, ischemic injury, and inflammation often bring about irreversible damage and loss of function to the CNS. Ischemic injury remains an important risk of neuron loss in the CNS. It has been reported that both endurance and resistance exercise training enhance cognitive performance148,149,150 and improve functional performance, such as balance and walking speed,151,152,153 in post-stroke population, implying that exercise promotes the repair of central neurons. Moreover, in the ischemic stroke rodent model, it has been confirmed that early endurance exercise, for instance wheel-running and treadmill training, contributes to functional and neuronal recovery, mainly improving motor function via enhancing synaptic plasticity,154 promoting myelin regeneration154 and neuron survival,155 and facilitating cerebral angiogenesis.156 Multiple sclerosis (MS) is another kind of CNS disorders characterized by oligodendrocyte loss and axonal degeneration/demyelination.157 Recently emerging research suggests that exercise has therapeutic benefits on the outcomes in the CNS for MS patients, including oligodendrogenesis, remyelination, and axonal regeneration.158

Spinal cord injury (SCI) disrupts both axonal pathways and segmental spinal cord circuitry, resulting in permanent loss of motor, sensory, and autonomic function. Exercise has been shown to induce synaptic plasticity and restore motor/sensory function in SCI patients.159 Subsequently, endurance exercise, such as treadmill training, has been reported to enhance axonal regeneration and sprouting in SCI rodent models via multiple ways.160,161,162 Of note, it has been revealed that the cholinergic neurotransmission from spinal locomotor neurons activates spinal NSPCs, leading to neurogenesis in the adult zebrafish. Interference with γ-aminobutyric acid signaling promotes functional recovery after spinal cord injury, which acts in a non-synaptic fashion to maintain NSPCs quiescence.163 Though it provides a new approach for locomotor networks’ activity-dependent neurogenesis during SCI regeneration, whether similar effects can be found in mammals needs to be further investigated. Currently, the multi-faceted regeneration strategies for SCI regeneration have been met with mixed success, however, adult neurogenesis in heterogeneous NSPC populations is still creating barriers to the function recovery of SCI. Indeed, NSPCs proliferate and differentiate into reactive astrocytes in the injured spinal cord, contributing to the glial scar border, which segregates the injury and prevents additional damage.164,165 However, this scar also prevents axonal outgrowth into the site of injury and generation of new cell types within the neural lesion.166 Thus, stem cell-based transplantation, including olfactory ensheathing cells (OECs), MSCs, and NSPCs, has opened an avenue for functional recovery of SCI, which has been enhanced by exercise training as well.167 It has been reported that exercise enhances the effect of OEC grafts in super acute thoracic cord transected rats, inducing a fourfold increase in regenerating axons within the caudal stump of the transected spinal cord.168 Additionally, exercise significantly promoted NSPCs graft survival and differentiation more into neurons and oligodendrocytes, enhancing myelination, and restoration of serotonergic fiber innervation in the lumbar spinal cord via reducing stress caused by active oxygen or active nitrogen through insulin-like growth factor 1 (IGF-1) signaling, which provided more theoretical basis for exercise rehabilitation and pharmacological mimetics169 (Fig. 1c).

운동으로 유도되는 중추신경계 재생

신경 줄기 및 전구 세포(NSPC)는

중추 신경계(CNS) 재생의 주요 촉진제로,

신경 발생을 통해 매우 특정한 신경 세포 네트워크로 이동하고 분화하며,

신경 교세포와 성상 세포는 신경 교세포 발생을 통해 생성됩니다.142

CNS 손상에 대한 NSPC의 반응은

매우 복잡하고 손상 정도와 위치에 따라 달라지기 때문에

내인성 성인 신경 발생은 많은 논란이 있어왔습니다.

최근 해마에는 노화에 따라 감소하지만

거의 전 생애에 걸쳐 계속 새로운 뉴런을 생성하는 성인 해마 신경발생(AHN)이라고 하는

NSPC가 존재한다는 사실이 확인되었습니다.143,144

복측 해마는 기분과 불안을 조절하는 신경 회로에서 중요한 뇌 영역입니다.해마의 상아질에 있는 성인 태생 뉴런은 독립적인 인코딩 단위로서 정보를 인코딩하고 성숙한 과립 세포를 억제하여 상아질의 전반적인 활동을 조절하는 것으로 제안되었습니다.신경 발생을 매개로 한 성숙한 세포의 억제는 기억 간섭을 줄이고 중립적인 상황과 두려운 상황 모두에서 역전 학습을 가능하게 할 수 있습니다.이렇게 향상된 역전 학습 능력과 인지적 유연성은 지속적인 위협이 없는 상황에서 안전한 환경을 두려운 것으로 인식하는 것에서 더 이상 안전한 환경을 두려움과 연관시키지 않는 것으로 전환하는 것을 촉진할 수 있습니다.치상회 기능과 인지 유연성 결함을 치료하는 것은 기분 및 불안 장애에 대한 새로운 치료 전략으로 유망할 수 있습니다. Abstract 성인 해마 신경 발생은 패턴 분리와 같은 인지 과정과 스트레스 및 항우울제의 행동 효과에 관여합니다. 젊은 성인에서 태어난 뉴런은 국소 뉴런을 모집하여 치아상교회의 전반적인 활동을 억제함으로써 맥락적 표현을 희박하게 하고 패턴 분리를 개선할 수 있는 것으로 나타났습니다. 우리는 신경 발생 매개 억제가 기억 간섭을 줄이고 중립적인 상황과 감정적으로 충전된 상황 모두에서 역전 학습을 가능하게 한다고 제안합니다. 이러한 인지적 유연성 향상은 불안과 우울과 같은 행동을 줄이는 데 도움이 될 수 있습니다.

해마의 상아질은 인간을 포함한 성체 포유류의 뇌에서 새로운 뉴런이 지속적으로 생성되고 국소 네트워크에 통합되는 개별 영역 중 하나입니다. 지난 10년간의 연구를 통해 상아질의 신경 발생 과정에 대한 이해가 이루어졌지만, 성체에서 태어난 상아 과립 세포(DGC)의 기능은 여전히 불분명합니다.출생 후 성체에서 태어난 DGC는 축삭과 수상돌기의 신생 성장과 구심성 및 구심성 시냅스의 형성을 포함한 긴 형태 형성 과정을 거칩니다. 성체에서 태어난 DGC는 뇌 회로에 완전히 통합되기 전에 향상된 흥분성과 가소성을 보입니다.성체에서 태어난 DGC가 국소 네트워크에 추가되는 것은 동물의 경험에 의해 광범위하게 조절되며, 이는 해마 활동을 불러일으킵니다. 해마 활동을 변화시키는 생리적 및 병리학적인 조건도 해마의 성인 신경 발생에 영향을 미칩니다. 동물의 경험, 특히 DGC가 성숙하는 동안 발생하는 경험은 완전히 성숙했을 때 이 세포의 반응성에 영향을 미칠 수 있습니다.여러 계산 연구에서 나온 일반적인 가설은 성인의 신경 발생이 가소성을 신생아의 미성숙 DGC에 대부분 국한시켜 성숙한 DGC가 표현하는 정보를 보존한다는 것입니다. 최근의 한 모델은 미성숙 DGC가 시간적으로 밀접하게 발생하는 사건을 연결하여 패턴 통합자 역할을 할 수 있다고 제안합니다.신경 발생 제거 모델과 행동 분석을 결합한 연구는 성체 해마 신경 발생의 기능에 관한 일관되지 않은 데이터를 산출했습니다. 특정 실험 조건의 차이 외에도 다양한 실험 일정과 평가된 기능의 유형이 이러한 불일치의 두 가지 주요 원인입니다.상이교는 패턴 분리에서 중요한 역할을 합니다. 패턴 유사성의 함수로서 패턴 분리에서 성체 신경 발생의 역할이 최근에 밝혀졌습니다.앞으로 성체 신경 발생의 기능적 메커니즘을 이해하기 위해서는 신경 발생을 조작할 수 있는 세포적, 시간적 정밀성을 갖춘 새로운 방법과 상아질 관련 기능을 직접 평가하는 행동 테스트가 필요할 것입니다. Abstract 성체에서 태어난 뉴런이 성체 해마의 회로에 통합되는 것은 학습과 기억에서 성체 해마 신경 발생의 중요한 역할을 시사하지만, 이러한 과정에서의 구체적인 기능은 여전히 밝혀지지 않았습니다. 이 글에서는 행동 연구를 기반으로 한 발전과 컴퓨터 모델링이 제공하는 통찰력을 포함하여 이 분야의 최근 진전을 요약합니다. 신생아 뉴런이 패턴 분리와 같이 특히 치상교에 의존하는 해마 기능에 관여할 수 있다는 증거가 점점 더 많이 제시되고 있습니다. 또한, 성숙 단계가 다른 신생아 뉴런은 학습과 기억에 뚜렷한 기여를 할 수 있습니다. 특히, 계산 연구에 따르면 신생아 뉴런이 완전히 성숙하기 전에는 시간적으로 밀접하게 발생하는 사건의 인코딩에 어느 정도 유사성을 도입하여 패턴 통합자 역할을 할 수 있다고 합니다.

노화 관련 신경 퇴행성 질환은

아마도 손상된 AHN과 관련이 있을 것입니다.

이러한 동물 연구에 따르면

자발적 운동은

해마 신경 생성을 촉진하고

이 뇌 구조에서 노화와 관련된 세포 증식 감소를 예방합니다.145,146

또한 운동이

사람의 좌측 해마에서 체적 유지를 유도한다는 사실도 밝혀져

지구력 운동 중재가 노화와 관련된 해마 기능 저하를 예방하는 데 유용합니다.147

노화 외에도

외상, 허혈성 손상 및 염증은

종종 CNS에 비가역적 손상과 기능 상실을 가져옵니다.

허혈성 손상은

중추신경계에서 신경세포 손실의 중요한 위험 요인으로 남아 있습니다.

지구력 및 저항성 운동 훈련은

모두 뇌졸중 후 인지 능력을 향상시키고148,149,150

균형 및 보행 속도와 같은 기능적 성능을개선하며151,152,153

운동이 중추 신경세포의 회복을 촉진한다는 보고가 있습니다.

또한 허혈성 뇌졸중 설치류 모델에서 바퀴 달리기 및 트레드밀 훈련과 같은 초기 지구력 운동은 주로 시냅스 가소성 강화를 통해 운동 기능을개선하고154 미엘린 재생과 신경세포 생존을촉진하며155 뇌 혈관 신생을 촉진하는 등 기능 및 신경세포 회복에 기여하는 것으로 확인되었습니다.156

다발성 경화증(MS)은

희돌기아교세포 손실과 축삭 변성/탈수초화를 특징으로 하는

또 다른 종류의 CNS 장애입니다.157

최근 새로운 연구에 따르면

운동은 희돌기아교세포 생성, 재수초화, 축삭 재생을 포함하여

MS 환자의 CNS 결과에 치료 효과가 있는 것으로 나타났습니다.158

척수 손상(SCI)은

축삭 경로와 분절 척수 회로를 모두 파괴하여

운동, 감각 및 자율 기능의 영구적 상실을 초래합니다.

운동은

시냅스 가소성을 유도하고

SCI 환자의 운동/감각 기능을 회복시키는 것으로 나타났습니다.159

그 후, 러닝머신 훈련과 같은 지구력 운동은 다양한 방법을 통해

SCI 설치류 모델에서 축삭 재생과 발육을 향상시키는 것으로 보고되었습니다.160,161,162

특히, 척추 운동 신경세포의 콜린성 신경 전달이

척추 NSPC를 활성화하여 성인 제브라피쉬에서 신경 발생을 유도한다는 사실이 밝혀진 바 있습니다.

γ- 아미노부티르산 신호의 간섭은

척수 손상 후 기능 회복을 촉진하며,

이는 비시냅스 방식으로 작용하여 NSPC의 정지를 유지합니다.163

이는 SCI 재생 중 운동 네트워크의 활동 의존적 신경 발생에 대한 새로운 접근 방식을 제공하지만

포유류에서도 유사한 효과를 찾을 수 있는지 여부는

더 조사할 필요가 있습니다.

현재 SCI 재생을 위한 다각적인 재생 전략은 다양한 성공을 거두었지만,

이질적인 NSPC 집단에서 성체 신경 발생은

여전히 SCI의 기능 회복에 장애가 되고 있습니다.

실제로 NSPC는 손상된 척수에서 증식하고 반응성 성상교세포로 분화하여 신경교 흉터 경계에 기여하여 손상을 분리하고 추가 손상을 방지합니다.164,165 그러나 이 흉터는 또한 손상 부위로의 축삭 성장과 신경 병변 내 새로운 세포 유형의 생성을 방지합니다.166 따라서 후각피복세포(OEC), 중간엽줄기세포(MSC), 신경세포(NSPC)를 포함한 줄기세포 기반 이식은 운동 훈련을 통해 SCI의 기능을 회복할 수 있는 길을 열었으며, 이는 운동 훈련으로도 향상되었습니다.167 운동은 초급성 흉수 절제 쥐에서 OEC 이식 효과를 향상시켜 절제된 척수의 꼬리 그루터기 내에서 재생 축삭의 4배 증가를 유도하는 것으로 보고되었습니다.168 또한 운동은 인슐린 유사 성장 인자 1(IGF-1) 신호를 통해 활성 산소 또는 활성 질소로 인한 스트레스를 감소시킴으로써 NSPC의 이식 생존과 신경세포 및 희돌기아교세포로의 분화를 크게 촉진하고 수초화를 강화하며 요추 척수의 세로토닌성 섬유 신경을 회복시켜 운동 재활 및 약리학 모방의 이론적 기반을 제공했습니다169 (그림 1c).

Exercise-induced regeneration in peripheral nervous system

The regenerative capacity of the nervous system varies considerably between the peripheral nervous system (PNS) and CNS. On the contrary, the adult human PNS retains the ability of axons to regenerate after injury and successfully reinnervate the intended target.170 In the PNS, injured nerves undergo successful Wallerian degeneration and subsequently the axons upstream of the injury undergo polarized growth toward their target tissues.171 Therefore, enhancing the regeneration of axons is often considered to be a therapeutic target for improving functional recovery after peripheral nerve injury. Several clinical studies have suggested exercise as a non-pharmacological approach to positively affect various aspects of peripheral neuropathy such as diabetic peripheral neuropathy (DPN),172,173 chemotherapy-induced peripheral neuropathy (CIPN),174,175 and even carpal tunnel syndrome.176 Among these studies, a 10-week composite training program of endurance and resistance exercise led to significant reductions in pain and neuropathic symptoms, and increased intraepidermal nerve fiber branching from a proximal skin biopsy in DPN patients.173 Similarly, the positive effects of exercise, including decreasing pain and improving physical function177 as well as improvement of deep sensitivity178 and static balance performance,179 have been confirmed in CIPN patients. The effect of exercise promoting peripheral nerve regeneration is also observed in animal models. Physiologically, ladder-based resistance training effectively induced similar growth in the radial and sciatic nerves (SN) of adult rats including myelinated axons CSA, unmyelinated axons CSA, myelin sheath thickness, and Schwann cells nuclei area.180 Meanwhile, the functional and histological recovery after the mouse SN crush was positively influenced by treatment with eccentric exercise.181 Moderate swimming training was found to promote nerve regeneration in SN ligation or SN transection mice as well.182,183 Additionally, treadmill training accentuated nerve regeneration, accelerated functional recovery and prevented muscle atrophy in median nerve crush injury rat models184 (Fig. 1d).

운동으로 인한 말초 신경계 재생

신경계의 재생 능력은

말초 신경계(PNS)와 중추 신경계(CNS)에 따라 상당히 다릅니다.

반면, 성인의 말초 신경계는

손상 후에도 축삭이 재생하여

의도한 표적을 성공적으로 재신경화하는 능력을 유지합니다.170

말초 신경계에서 손상된 신경은

성공적인 월러리안 퇴행을 겪고,

이후 손상 상류의 축삭은 목표 조직을 향해 양극화된 성장을 합니다.171

따라서

축삭의 재생을 강화하는 것이

말초 신경 손상 후 기능 회복을 개선하는 치료 목표로 간주되는 경우가 많습니다.

여러 임상 연구에서 당뇨병성 말초 신경병증(DPN),172,173 화학요법 유발 말초 신경병증(CIPN),174,175, 심지어 손목 터널 증후군과 같은 말초 신경병증의 다양한 측면에 긍정적인 영향을 미치는 비약물학적 접근법으로 운동을 제안했습니다.176 이러한 연구 중 지구력 운동과 저항 운동의 10주 복합 훈련 프로그램은 DPN 환자의 근위부 피부 생검에서 통증과 신경병증 증상의 현저한 감소와 표피 내 신경 섬유 분지의 증가로 이어졌습니다.173

마찬가지로,

통증 감소와 신체 기능 개선177, 심부 감각178 및 정적 균형 능력향상179 등

운동의 긍정적인 효과는 CIPN 환자에서 확인되었습니다.

말초 신경 재생을 촉진하는 운동의 효과는 동물 모델에서도 관찰됩니다. 생리적으로 사다리 기반 저항 훈련은 성인 쥐의 요골 및 좌골 신경(SN)에서 골수화 축삭 CSA, 비골수화 축삭 CSA, 수초 두께 및 슈반 세포 핵 면적을 포함하여 유사한 성장을 효과적으로 유도했습니다.180 한편, 마우스 SN 분쇄 후 기능 및 조직학적 회복은 편심 운동 치료에 의해 긍정적인 영향을 받았습니다.181 적당한 수영 훈련은 SN 결찰 또는 SN 절개 마우스에서도 신경 재생을 촉진하는 것으로 밝혀졌습니다.182,183 또한 트레드밀 훈련은 신경 재생을 강조하고 기능 회복을 가속화하며 중앙 신경 분쇄 손상 쥐 모델184에서 근육 위축을 예방했습니다 (그림 1d).

Exercise-induced regeneration of other tissues

The liver exhibits the unique regenerative capacity that ensures body homeostasis or post-injury repair.185 Experimental models that involve partial hepatectomy or chemical injury have revealed the efforts of exercise that make the liver return to equivalent size and weight to those prior to injury. It has been reported that a 4 weeks endurance exercise program markedly enhances the ischemic tolerance and the regenerative capacity of fatty liver in diet-induced steatosis mice.186 Moreover, Fard-Aghaie et al.187 confirmed that a novel physical prehabilitation of treadmill training promoted hepatocyte proliferation and enhanced mitochondrial biogenesis, restoring liver function after partial hepatectomy operation in rodent models. Although the liver is a solid organ with a high regenerative capacity, the rate of physiological cell turnover is very slow. Thus, the regenerative activities of hepatocytes and cholangiocytes induced by exercise provides new strategies for restoring liver function (Fig. 1g).

The skin, the largest organ of the human body, defends against daily assaults from the external environment. In general, scarring and regeneration are two physiologically opposite endpoints to skin injuries. Thus, scarless regeneration is the ultimate goal in repairing skin injury. Indeed, emerging evidence has shown exercise promotes skin wounds healing. For example, endurance exercise improves cutaneous wound healing rates of different etiologies in mice and humans.188,189,190 Interestingly, a study of mice trained on a motorized treadmill has suggested that different intensities of exercise have different impacts on healing rates.191 In addition, another study has shown that low-intensity exercise accelerates wound healing rates in diabetic mice but high-intensity exercise fails.192 However, promoting wound healing is not the same as promoting skin regeneration, as there are few studies for further cellular mechanisms. Whether exercise promotes resident skin stem cell proliferation remains unclear.

Exercise offers regenerative effects to the hematopoietic system as well. In this regard, preclinical studies of treadmill exercise training in mouse models have demonstrated endurance exercise is able to modify the bone marrow microenvironment, alter hematopoiesis, and accelerate hematopoietic regeneration.193,194 Leukocytes derive from hematopoietic stem and progenitor cells (HSPCs), acting as a major responder of exercise. Recently it has been reported that running exercise diminishes leptin production in adipose tissue to regulate HSPCs proliferation and leukocyte production in mice.195 The impact of exercise on leukocyte production and on HSPC epigenome and transcriptome persists for several weeks. Curiously, it was also showed that ultra-endurance exercise contributed to an increase in circulating leukocytes and induced an inflammatory response that resulted in a highly significant decline of circulating hematopoietic progenitor cells functionality in humans.196 This may be the result of different inflammatory effects of the organism in response to different exercise intensities and patterns. Hematopoietic stem cell transplantation (HSCT) is increasingly used for hematological malignancies or severe non-malignant hematological disorders. Since exercise is convinced to affect HSPC, HSCT combined with exercise therapy is also a topic worth being explored to improve prognosis.197 Lisio et al.198 demonstrated a survival benefit and increased total blood reconstitution in mice that were pre-conditioned with endurance exercise after bone marrow transplantation. However, as implementation varies across studies in terms of timing of exercise initiation, exercise types and duration of exercise according to potential benefits of exercise reported by previous studies, the efficacy of exercise program among HSCT patients varies.199,200 The efficacy of exercise promoting HSCT is worthy of recognition, however, further mechanistic studies are needed (Fig. 1e).

Molecular mechanisms of tissue regeneration induced by exercise

In response to exercise, the organism will have both structural and functional adaptive changes which confer the beneficial effect of exercise. However, the mechanisms by which exercise initiates cellular responses involved in tissue repair/regeneration are still inadequately understood. Generally, exercise predominantly leads to an increase in mechanical signals such as fluid flow, dynamic tension, compression, and hydrostatic pressure. Thus, mechanotransduction, the process by which the organism converts mechanical loading into cellular responses, is regarded as one kind of potent signaling pathways for adaptive responses to exercise.201 Besides mechanical signals, numerous studies have shown that a range of bioactive substances regulated by exercise (namely, exerkines) contribute to maintaining homeostasis and improving the impaired function of diverse organs.202,203 These exerkines can be secreted by a variety of cells, including satellite cells, osteoblasts, immune cells, endothelial cells, fibroblasts, macrophages, and even adipocytes, which act as autocrine, paracrine, or circulating regulators in response to exercise.204,205 Notably, it has been extensively investigated that both mechanical stress and biochemical signals are involved in promoting cell proliferation and renewal induced by exercise.206,207,208,209,210 Since the complicated mechanism of exercise-induced tissue regeneration advances rapidly, we will discuss in detail the substantial novel progress in the regulation of tissue regeneration from multiple aspects.

운동으로 유도되는 조직 재생의 분자 메커니즘

운동에 대한 반응으로 유기체는 운동의 유익한 효과를 부여하는 구조적 및 기능적 적응 변화를 겪게 됩니다. 그러나 운동이 조직 복구/재생과 관련된 세포 반응을 일으키는 메커니즘은 아직 제대로 이해되지 않았습니다. 일반적으로 운동은 주로 유체 흐름, 동적 장력, 압축 및 정수압과 같은 기계적 신호의 증가로 이어집니다. 따라서 유기체가 기계적 부하를 세포 반응으로 전환하는 과정인 기계 전달은 운동에 대한 적응 반응을 위한 강력한 신호 경로의 한 종류로 간주됩니다.201 기계적 신호 외에도 수많은 연구에 따르면 운동에 의해 조절되는 다양한 생리 활성 물질(즉, 엑서킨)이 항상성을 유지하고 다양한 기관의 손상된 기능을 개선하는 데 기여합니다.202,203 이러한 엑서카인은 위성 세포, 조골 세포, 면역 세포, 내피 세포, 섬유 아세포, 대식 세포, 심지어 지방 세포를 포함한 다양한 세포에서 분비되어 운동에 반응하여 자율 신경, 파라크린 또는 순환 조절제 역할을 합니다.204,205 특히 운동에 의해 유도된 세포 증식 및 재생 촉진에는 기계적 스트레스와 생화학적 신호가 모두 관여한다는 사실이 광범위하게 연구되고 있습니다.206,207,208,209,210 운동에 의한 조직 재생의 복잡한 메커니즘은 빠르게 발전하고 있으므로 조직 재생 조절의 실질적인 새로운 진보에 대해 여러 측면에서 자세히 논의하겠습니다.

Mechanotransduction

Indeed, a variety of cell surface proteins and structures, named mechanosensors, has been proposed to convert these mechanical stimuli into electrical or biochemical signals. The Piezo family, one of the mechanically activated ion channel, has emerged as the critical mechanosensors in many cell types, responding to various forms of mechanical forces, including membrane stretch, static pressure, and fluid shear stress.211,212,213 Of note, Piezo1 is also highly expressed in osteocytes and can be upregulated by mechanical stretching, involved in stem cell differentiation and bone formation.214,215,216 In addition, Piezo1 channels, working as non-selective cationic channels in endothelial cells, had profound importance for shear stress-evoked Ca2+ signaling, sensing the exercise induced changes in blood flow.217 Focal adhesions, one type of integrin-based adhesion complex, is another important mechanosensor of transmitting mechanical signals and promoting protein biosynthesis.218,219,220 Unlike integrin-based adhesions that receive mechanical stimuli from the extracellular matrix, gap junctions, two juxtaposed connexons on the surfaces of adjacent cells, are bridges for mechanical signaling communication between cells. Multiple types of connexins play a role in responding to the mechanotransduction, among which connexin 43 was shown that its knockout in early osteoblasts caused impaired muscle formation in mice.221,222 Moreover, low density lipoprotein receptor-related proteins 5/6 (LRP5/6), the single-pass transmembrane protein, have been found to act as the receptor of Wnt ligands and be indispensable for Wnt/β-catenin signaling transduction, which has been shown to affect bone mass by regulating osteoblast proliferation and activity.223,224,225 Besides these canonical membrane structures, novel mechanosensitive proteins are regularly discovered, such as the recent discovery of plexin D1 as a mechanosensitive receptor,226 with more likely awaiting discovery. Taken together, these important membrane structures are the cornerstone of various cellular responses to external mechanical stimuli, and may be another prelude to unlocking the secrets of exercise induced regeneration.

Within the help of the mechanosensors, the activation of sequential signaling cascades and expression‎ of downstream target genes exhibit some common features, even in various cell types, including osteocytes,227 myocytes,228 neurons,229,230 liver cells,231,232 and cardiomyocytes.233,234 Basically, signal transduction can occur through the direct physical connections between the membrane, the cytoskeleton, and the nucleus, triggering gene expression‎ and protein synthesis.235 Importantly, the transmission of information still involves facilitating biochemical signals via intracellular signaling molecules and secondary messengers. The activation of Wnt/β-catenin pathway has been proven to be a key regulator of cell growth. Recently a multi-omic analysis of stretched osteocytes has uncovered mechanically stimulated osteocytes support bone regeneration via ossification and extracellular matrix remodeling, focusing on the activation of Wnt/β-catenin pathway in both human and murine cells, showing the conservation of mechanotransduction mechanisms.236 It has been established that exercise-induced loading reduces expression‎ of sclerostin (SOST) and Dickkopf-related protein 1 (Dkk1), the inhibitors of the Wnt pathway, in osteocytes, thus stimulating new bone formation.237 Focal adhesion kinase (FAK), an attachment protein associated integrin-based adhesion complex, has also been a key component of transmitters of mechanical signals. FAK was reported to be required for IGF-1-induced muscle hypertrophy, through tuberous sclerosis complex 2 (TSC2)/mammalian target of rapamycin (mTOR)/ribosomal S6 kinase 1 (S6K1)-dependent signaling pathway.238 Interestingly, fluid flow shear stress could trigger FAK dephosphorylation, driving class IIa histone deacetylase 5 (HDAC5) nuclear translocation, which demonstrated a role for HDAC5 in loading-induced SOST suppression.239 Another most described mediators are the transcriptional coactivators yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ).240 Generally, YAP and TAZ, known to be regulated by FAK through RhoA-mediated contractile force, translocate from the cytoplasm to the nucleus in cells perceiving high levels of mechanical signaling.241,242 Notably, nuclear translocation of YAP/TAZ has been also regulated by Hippo signaling pathway.243,244 Multiple mechanical stimuli mostly inhibit the Hippo pathway, promoting YAP/TAZ to enter the nucleus to activate genes involved in the cell cycle and cell proliferation.245,246 Thus, suppression of Hippo signaling play an important role in promotion of tissue regeneration as well, suggesting a new intervention mechanism for exercise-induced regeneration.247,248 Furthermore, Notch signaling has been shown to be another associated pathway of mechanotransduction as well.249 Generally, mechanical loading sensed by integrins or mechanosensitive Piezo results in the transcription of ligands of sending cell, regulating Notch signaling of receiving cell, which modulates cell proliferation and differentiation.250 It has been reported that Notch signaling is impaired in regenerating aged skeletal muscle, which can be restored by physiological stimuli of exercise.251,252,253 Therefore, further researches should be carried out to demonstrate the underlying mechanisms of mechanotransduction mediated tissue regeneration with different exercise types, which may provide the novel targets for clinical interventions (Fig. 2).

기계 전달

실제로 이러한 기계적 자극을 전기적 또는 생화학적 신호로 변환하는 다양한 세포 표면 단백질과 구조가 메카노센서라고 불리는 것으로 제안되었습니다.

기계적으로 활성화되는 이온 채널 중 하나인

피에조 계열은

막 신축, 정압, 유체 전단 응력 등 다양한 형태의 기계적 힘에 반응하여

많은 세포 유형에서 중요한 메카노센서로 부상했습니다.211,212,213

특히

피에조1은 조골세포에서도 높게 발현되며

기계적 신축에 의해 상향 조절되어 줄기세포 분화 및 뼈 형성에 관여할 수 있습니다.214,215,216

또한 내피 세포에서 비선택적 양이온 채널로 작용하는 피에조1 채널은

전단 응력 유발 Ca2+ 신호에 매우 중요하여 운동에 의한 혈류 변화를 감지합니다.217

인테그린 기반 접착 복합체의 한 유형인 국소 접착은 기계적 신호를 전달하고 단백질 생합성을 촉진하는 또 다른 중요한 기계 센서입니다.218,219,220 세포 외 기질로부터 기계적 자극을 받는 인테그린 기반 접착과 달리, 인접한 세포 표면에 나란히 있는 두 개의 커넥손인 갭 접합은 세포 간의 기계적 신호 통신을 위한 가교 역할을 합니다. 여러 유형의 코넥신이 기계 전달에 반응하는 역할을 하며, 그 중 코넥신 43은 초기 조골세포에서 녹아웃되면 생쥐의 근육 형성에 장애를 일으키는 것으로 나타났습니다.221,222 또한, 단일 통과 막 단백질인 저밀도 지단백질 수용체 관련 단백질 5/6(LRP5/6)은 Wnt 리간드의 수용체로 작용하여 Wnt/β-카테닌 신호 전달에 필수적인 것으로 밝혀졌으며, 이는 조골세포 증식 및 활성을 조절하여 골량에 영향을 미치는 것으로 나타났습니다.223,224,225 이러한 표준 막 구조 외에도 최근 기계감응성 수용체로서 플렉신 D1이 발견되는 등 새로운 기계감응성 단백질이 정기적으로 발견되고 있으며,226 더 많은 단백질이 발견되기를 기다리고 있습니다. 종합하면, 이러한 중요한 막 구조는 외부 기계적 자극에 대한 다양한 세포 반응의 초석이며, 운동 유도 재생의 비밀을 푸는 또 다른 서막이 될 수 있습니다.

메카노센서의 도움으로 순차적 신호 캐스케이드의 활성화와 하류 표적 유전자의 발현은 골세포,227 근세포,228 뉴런,229,230 간세포,231,232 및 심근 세포를 포함한 다양한 세포 유형에서도 몇 가지 공통된 특징을 나타냅니다.233,234 기본적으로 신호 전달은 세포막, 세포 골격 및 핵 사이의 직접적인 물리적 연결을 통해 발생하여 유전자 발현과 단백질 합성을 촉발할 수 있습니다.235 중요한 것은 정보 전달에는 여전히 세포 내 신호 분자와 이차 전달자를 통한 생화학적 신호 촉진이 포함된다는 점입니다. Wnt/β-카테닌 경로의 활성화는 세포 성장의 핵심 조절자라는 것이 입증되었습니다. 최근 신장된 조골세포의 다중 오믹스 분석을 통해 기계적으로 자극된 조골세포가 골화 및 세포 외 기질 리모델링을 통해 뼈 재생을 지원하며, 인간과 쥐 세포 모두에서 Wnt/β-catenin 경로의 활성화에 초점을 맞추어 기계 전달 메커니즘의 보존을 보여주는 것이 밝혀졌습니다.236 운동으로 인한 부하가 골세포에서 Wnt 경로의 억제제인 클레로스틴(SOST)과 딕코프 관련 단백질 1(Dkk1)의 발현을 감소시켜 새로운 뼈 형성을 촉진한다는 사실이 밝혀졌습니다.237 부착 단백질 관련 인테그린 기반 접착 복합체인 국소 접착 키나제(FAK)도 기계적 신호 전달의 핵심 요소로 여겨져 왔습니다. FAK는 결절성 경화증 복합체 2(TSC2)/포유류 라파마이신 타겟(mTOR)/리보솜 S6 키나제 1(S6K1)-의존 신호 경로를 통해 IGF-1에 의한 근육 비대에 필요한 것으로 보고되었습니다.238 흥미롭게도 유체 흐름 전단 응력은 FAK 탈인산화를 유발하여 클래스 IIa 히스톤 탈아세틸화 효소 5(HDAC5) 핵 전위를 유도할 수 있으며, 이는 부하로 인한 SOST 억제에서 HDAC5의 역할을 입증했습니다.239 가장 많이 설명된 또 다른 매개체는 전사적 활성제 예-연관 단백질(YAP)과 PDZ 결합 모티프 전사적 활성제(TAZ)입니다.240 일반적으로 RhoA 매개 수축력을 통해 FAK에 의해 조절되는 것으로 알려진 YAP와 TAZ는 높은 수준의 기계적 신호를 감지하는 세포에서 세포질에서 핵으로 이동합니다.241,242 특히, YAP/TAZ의 핵 전위는 히포 신호 경로에 의해서도 조절됩니다.243,244 여러 기계적 자극은 대부분 히포 경로를 억제하여 YAP/TAZ가 핵으로 들어가 세포 주기 및 세포 증식에 관여하는 유전자를 활성화하도록 촉진합니다.245,246 따라서 히포 신호의 억제는 조직 재생 촉진에도 중요한 역할을 하여 운동 유발 재생의 새로운 개입 메커니즘을 제시합니다.247,248 또한, Notch 신호는 기계 전달의 또 다른 관련 경로로 밝혀졌습니다.249 일반적으로 인테그린 또는 기계감응 피에조에 의해 감지된 기계적 부하는 송신 세포의 리간드 전사를 초래하여 수신 세포의 Notch 신호를 조절하여 세포 증식 및 분화를 조절합니다.250 노화된 골격근을 재생할 때 노치 신호 전달이 손상되며, 이는 운동의 생리적 자극에 의해 회복될 수 있다고 보고되었습니다.251,252,253 따라서 다양한 운동 유형으로 기계 전달 매개 조직 재생의 기본 메커니즘을 입증하는 추가 연구가 수행되어야 임상 개입을위한 새로운 표적을 제공 할 수 있습니다 (그림 2).

Fig. 2

Mechanotransduction regulating regenerative responses. The signaling transduction of exercise-induced regeneration are generally initiated by mechanical signals. A series of membrane receptors or channels can respond to mechanical signals, thereby converting mechanical signals into chemical molecular signals. Piezo1 channels, working as non-selective cationic channels, sense the exercise-induced stress, converting into mechanical stress-evoked Ca2+ signaling. Integrin-based adhesion complex activates FAK, promoting YAP/TAZ translocation via inhibiting Hippo signaling. FAK can drive HDAC5 nuclear translocation and suppress SOST. Integrins or Piezo channels activate the transcription of ligands of Notch receptor in sending cell, triggering Notch signaling of receiving cell. Wnt/β-catenin pathway is important in osteogenesis, which can be inhibited by SOST. Connexin 43 responds to the mechanotransduction for cell-to-cell communication. Created with BioRender

재생 반응을 조절하는 기계 전달. 

운동으로 유도된 재생의 신호 전달은 일반적으로 기계적 신호에 의해 시작됩니다. 일련의 막 수용체 또는 채널은 기계적 신호에 반응하여 기계적 신호를 화학적 분자 신호로 변환할 수 있습니다. 비선택적 양이온 채널로 작동하는 피에조1 채널은 운동으로 인한 스트레스를 감지하여 기계적 스트레스로 유발된 Ca2+ 신호로 변환합니다. 인테그린 기반 접착 복합체는 FAK를 활성화하여 히포 신호 억제를 통해 YAP/TAZ 전위를 촉진합니다. FAK는 HDAC5 핵 전위를 유도하고 SOST를 억제할 수 있습니다. 인테그린 또는 피에조 채널은 송신 세포에서 노치 수용체의 리간드 전사를 활성화하여 수신 세포의 노치 신호를 촉발합니다. Wnt/β-카테닌 경로는 골 형성에 중요하며, 이는 SOST에 의해 억제될 수 있습니다. 커넥신 43은 세포 간 통신을 위한 기계 전달에 반응합니다. BioRender로 제작

PI3K/Akt signaling pathway

Emerging evidence has revealed the essential contribution of PI3K/Akt signaling pathway to exercise-induced regeneration.254,255 An array of growth factors has been reported to act as exerkines, such as IGF-1,256 brain-derived neurotrophic factor (BDNF),257 epidermal growth factor (EGF)258 and their associated family, triggering the cellular responses via PI3K/Akt pathway. Amongst all the growth factors induced by exercise, the most widely studied is IGF-1. Notably, circulating IGF-1 is primarily secreted by the liver, while peripheral tissues, including bone and muscle, produce IGF-1 as well, acting in a paracrine/autocrine fashion. Exercise-induced IGF-1 locally leads to the sequential activation of PI3K/Akt signaling pathways with consequent induction of myoblasts,259,260 osteocytes261,262 and cardiomyocytes263,264 proliferation and differentiation. Meanwhile, neuregulin 1 (NRG1), a member of EGF family, and its tyrosine kinase receptor ErbB family is found to promote cell growth and differentiation physiologically and pathologically by targeting PI3K/Akt pathway.265,266,267 Moreover, BDNF and its receptor, tropomyosin-related kinase B (TrkB) mediate PI3K/Akt pathway as well, sharing the similar effects.268,269 BDNF has been discovered to be time-dependently upregulated in rat skeletal muscle after acute endurance exercise, which is convinced to be involved in exercise-induced skeletal muscle regeneration.257 Briefly, exercise-induced BDNF expression‎ also plays a crucial role in neuronal survival, proliferation, maturation, and outgrowth in both the brain,270,271,272,273 spinal cord,274,275 and PNS.276,277 Angiogenesis has also played a vital role in human physiology of tissue repair, since oxygen supply and nutrients constitute important primitive materials for tissue anabolic activity.278,279,280 The transcription of vascular endothelial growth factor (VEGF) a kind of pro-angiogenic factor, is mainly activated by exercise-induced hypoxia and mechanical stress, which plays a crucial role in endothelial cell survival and promotion of capillary sprouting via PI3K/Akt pathway.281,282 Several studies have revealed that both endurance and resistance exercise increase the expression‎ of VEGF in the brain, heart, skeletal muscle, and bones.95,283,284 HIIT training contributed to an overall increase in the expression‎ levels of VEGF and VEGF receptor-2 (VEGFR2) in skeletal muscle of subjects with peripheral myopathy associated with heart failure, promoting muscle capillarization,285 and differentially expressed genes of the skeletal muscle showed the PI3K/Akt signaling pathway was activated in response to HIIT.286 Of note, it has been found that the PI3K/Akt axis is not only activated by a range of exerkines mentioned above, but also in response to mechanical stress.287,288,289 Exercise frequently mediates crosstalk between mechanoregulation of regeneration and canonical regenerative signaling pathways. While Akt has been reported to be activated by Notch, a important role in mechanotransduction, in EPCs after endurance exercise in hypertension patients, targeting endothelial nitric oxide synthase, for restoration of impaired angiogenesis capacity of late EPCs.290

The downstream responses of PI3K/Akt pathway are also varied. One of the significant targets of Akt is mTOR, an evolutionarily conserved serine/threonine kinase. Actually, mTOR exists in two distinct complexes: mTOR complex 1 and mTOR complex 2 (mTORC1 and 2).291 The activation of mTORC1 is frequently spotted in the adaptive response to exercise.292 Importantly, the activation of mTOR-axis has been the critical process of exercise-induced regeneration in different tissues, including muscle,293,294 heart,295 brain296 and spinal cord.297 Mostly, mTORC1 phosphorylates and activates S6K1/2 and eukaryotic translation initiation factor 4E (eIF4E)-binding proteins 1 and 2 (4E-BP1/2), which contribute to stimulation of mRNA translation, thereby regulating increases or decreases in anabolic and catabolic processes.298 Additionally, the activation of mTORC1 suppresses autophagy and perhaps other lysosomal functions.299 For instance, NRG1 activated PI3K/Akt axis, targeting mTOR-pathway in hippocampal neurogenesis, which was confirmed by exercise-induced expression‎ of autophagy-related proteins.300 Moreover, CCAAT/enhancer binding protein β (C/EBPβ)-Cbp/p300-interacting transactivator with ED-rich carboxy-terminal domain 4 (CITED4) axis has been identified as critical modulator in the cardiomyocyte proliferation in adult exercised hearts, which has also been shown to be regulated by Akt.123,301 It has been confirmed that C/EBPβ is downregulated by endurance exercise to enhance cardiomyocyte proliferation via negatively regulating CITED4 in vitro.123 C/EBPβ and CITED4 has been reported to be regulated in myocardial ischemia or transverse aortic constriction murine models after exercise training.39,302,303 Overall, CITED4 acts as downstream of C/EBPβ, thereby activating the mTOR pathway, promoting exercise-induced cardiomyocyte proliferation and protecting from adverse cardiac remodeling.303,304,305 Another potential downstream mediator of the cell proliferation and development induced by exercise are forkhead box class O family (FOXOs). Akt/FOXO3a signaling pathway is activated in exercise-induced autophagy, which is beneficial for remedying sarcopenia.306 Akt is also likely to mediate FOXO family inhibition in the regulation of stem cell proliferation.307 Inhibition of FOXOs activity decreases myostatin expression‎ and increases satellite cell proliferation, and fusion, and leads to muscle hypertrophy308,309 (Fig. 3).

Fig. 3

PI3K/Akt signaling pathway. The PI3K/Akt pathway is mainly activated by an array of growth factors, such as IGF-1, NRG1, VEGF, and BDNF. Akt can be directly activated by Notch signaling. The PI3K/Akt pathway mainly acts as the upstream of mTOR activation. The activation of mTOR promotes cardiomyogenesis, myogenesis, and neurogenesis via various signaling. Importantly, PI3K/Akt axis inhibits C/EBPβ, thus upregulating CITED4 to activate mTOR and promoting myogenesis. Additionally, the PI3K/Akt axis inhibits FOXOs, promoting myogenesis. eNOS is upregulated by the PI3K/Akt axis, promoting angiogenesis. Created with BioRender

MAPK signaling pathways

The extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK), as key members of MAPK family, are also serine/threonine protein kinases that are irreplaceable players participating in diverse biological activities.310 Similar to PI3K/Akt signaling, MAPK signaling can be activated by a range of growth factors, thus playing an important role in exercise-induced tissue regeneration. More recently, it has been investigated that NRG1/ErbB2 signaling mediates the interaction of YAP with nuclear-envelope and cytoskeletal components for cardiomyocytes regeneration via the activation of ERK.311 Besides, MAPK/ERK signaling is also targeting the regulation of the cell cycle. Postnatal cell cycle exit is often accompanied by reduced expression‎ of cyclins and cyclin-dependent kinases.312,313,314 Endurance exercise up-regulated cyclin-dependent kinase 4 and Cyclin D1 by ERK signaling, inducing the proliferation and differentiation of endogenous neural stem cells, and improving neural function of rats with cerebral infarction.315 Exercise was also reported to activate MAPK/ERK signaling to promote cycling of satellite cells.294 Furthermore, running exercise accelerated muscle regeneration in aged mice, suppressing transforming growth factor-β (TGF-β)/Smad3 signaling in quiescent muscle stem cells via the restoration of Cyclin D1.316 Additionally, it has also been well-known that bone morphogenetic proteins (BMPs), members of TGF-β super family, are upregulated in bones and cartilages after exercise.317,318,319 Mostly, the regulation of downstream networks of BMPs signaling is specifically though canonical Smad-dependent pathways.320 Importantly, BMP signaling has played a vital role in osteoblast differentiation, which promotes osteoblastogenesis through p38 MAPK pathway as well.321,322,323 Furthermore, following repeated bouts of eccentric cycling, it was reported that phosphorylation of JNK and p38 MAPK were also activated in skeletal muscle, inducing the overexpression‎ of MyoD, myogenic regulatory factors (MRFs) and Myogenin324 (Fig. 4).

Fig. 4

MAPK signaling pathway. The MAPKs signaling can be activated by exercise-induced mechanical stress and a range of growth factors, including NRG1, TGF-β and BMP, thus playing an important role in exercise-induced tissue regeneration. MAPK/ERK signaling activates YAP translocation into nucleus, promoting cardiomyogenesis. The activation of ERK also promotes neurogenesis and cycling of satellite cells. The restoration of cyclin D1 inhibits TGF-β/Smad signaling. The p38 MAPK and JNK can activate the transcription factors that initiate the expression‎ of osteogenetic and myogenetic genes, including Myod, MRF, and Myogenin, promoting osteogenesis and myogenesis. Created with BioRender

AMPK/SIRT1/PGC-1α signaling pathway

Peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α) is commonly expressed in high-energy-demanding tissues such as heart, muscle, and brown adipose tissue, which is already considered as the core regulator of metabolic regulating pathways such as the adenosine monophosphate-activated protein kinase (AMPK)-sirtuin 1 (SIRT1)-PGC-1α pathway.325 Undoubtedly, exercise leads to the activation of AMPK in vivo through the modulation of the AMP-to-ATP ratio.326,327 Though PGC-1α mainly involved in mitochondrial biosynthesis and cellular respiration, has been reported to act as a vital regulator in cell proliferation and differentiation as well.67,328 Exercise strongly induces overexpression‎ of PGC-1α in both human and rodent muscle,329,330 which may trigger a remodeling of the satellite cells niche by altering the extracellular matrix composition, including the levels of fibronectin, thus affecting the proliferative output of satellite cells.331 While in terms of osteogenesis, PGC-1α has already been shown to play an important role in skeletal homeostasis by coactivating a range of transcription factors.332 Overexpression‎ of PGC-1α was sufficient to enhance osteocytic gene expression‎ in IDG-SW3 cells, murine primary osteoblasts, and osteocytes, and ex vivo bone cultures.333 In addition, deletion of PGC-1α suppressed differentiation and activity of osteoblast, resulting in a significant decrease of cortical thickness and trabecular thickness.334 Recently, it has been found that running exercise increases the expression‎ of PGC-1α in the hippocampus of depressed mice, targeting for antidepressant treatment via promoting the proliferation parvalbumin-positive interneurons.335 Mechanically, PGC-1α activates a variety of metabolic programs in different tissues through its ability to form heteromeric complexes with many nuclear hormone receptors, such as PPARs336 and estrogen-related receptors (ERRs).337 Interestingly, PGC-1α is regulated by AMPK/SIRT1 axis, promoting exercise-induced tissue regeneration, as well as involved in mitochondrial signaling,338,339 Thus PGC-1α has acted as a vital regulator in the adaptive response to exercise, which may be the key regulator of the cross-talk between mitochondrial biogenesis and exercise-induced regeneration (Fig. 5).

Fig. 5

AMPK/SIRT1/PGC-1α signaling pathway. Exercise changes the energy status, consuming a large amount of ATP, which elevates AMP-to-ATP ratio. Consequently, AMPK/SIRT1/PGC-1α signaling pathway is activated. PGC-1α is very important in the anabolic process of exercise-induced response. PGC-1α and PPAR/ERR form co-transcriptional complexes that initiate the overexpression‎ of target genes, thereby promoting tissue regeneration and repair, including neurogenesis, myogenesis, and osteogenesis. Created with BioRender

Noncoding RNAs and their regulated signaling pathways

Recently emerging evidences support the critical role of noncoding RNAs, another important cluster of exerkines, in the regulation of exercise-induced tissue regeneration. Among them, microRNAs (miRNAs) have shown significant changes in the musculoskeletal system after exercise training.340 It was reported that in healthy untrained males, miR-1, miR-133, and miR-181a were increased in skeletal muscle samples collected 3 h following 60 min of cycling at 70% of VO2 peak.341 Similarly, the former two were shown to decrease in skeletal muscle miRNA profiles of muscle atrophy mice.342,343 Indeed, miR-1 promotes myoblast differentiation, whereas miR-133 stimulates myoblast proliferation. Mechanically, miR-1 modulated myocyte enhancer factor 2 (MEF2) via suppressing HDAC4 and miR-133 inhibited serum response factor (SRF), promoting myogenesis in different stages.344 Of note, miR-1 also positively promoted the protein synthesis and myogenesis by targeting IGF-1/Akt/FOXO3 signaling pathway.345,346 More recently, liver-derived extracellular vesicle miR-122-5p after treadmill training was reported to promote angiogenesis through shifting substrate preference to fatty acids in endothelial cells by targeting 1-acyl-sn-glycerol-3-phosphate acyltransferase (AGPAT1), increasing capillary density in the quadriceps, and accelerating wound healing in mice.347 In addition, treadmill exercise training has been also reported to influence the miRNA profiles of bone tissue, such as miR-190a-5p, miR-203-5p, miR-27a-5p, and miR-5118.348 Importantly, miR-27a-5p is confirmed as a member of miR-23a cluster. The components of the miR-23a cluster regulated osteoblast differentiation by targeting the modulation of SOST via TGF-β signaling pathway, which may explain the regulation of exercise-induced osteogenesis by miRNAs.349 Moreover, more miRNAs have been identified to involve in the different process of fracture healing, thus, whether these miRNAs are regulated by exercise still deserves further exploration.350

Likewise, a wide range of miRNAs have been found to increase in exercised heart as well, acting as vital regulators of exercise-induced cardiomyocyte proliferation and involving in myocardial injury repair. Expression‎ of the protein kinase HIPK1 was identified as a direct target of miR-222 with anti-proliferative effects in cardiomyocytes, contributing to exercise-induced cardiomyogenesis.124,131 MiR-17-3p positively regulated cardiomyocytes proliferation and hypertrophy by targeting tissue inhibitor metallopeptidase 3 (TIMP3) and acting upstream of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/Akt signaling pathway, protecting against myocardial ischemia–reperfusion injury.133 Additionally, aerobic exercise training increased miR-26 and decreased miR-16, significantly promoting cardiomyocyte hypertrophy and proliferation via Akt/mTOR signaling pathway.351 Furthermore, miR-34a, regulated by adenosine deaminases acting on RNA 2 (ADAR2), contributed to exercise-induced cardiomyocyte proliferation, targeting SIRT1, Cyclin D1 and Bcl2.352

While in terms of exercise-induced adult neurogenesis, it was reported that running exercise downregulated miR-135a-5p, targeting inositol 1,4,5-trisphosphate (IP3) signaling, thus increasing proliferation of neural precursor cells of the mouse dentate gyrus.353 It was also shown that miR-199a-3p increased in spinal cord after SCI and miR-21 increased in SCI animals that had undergone exercise.354 It was confirmed that miR-21 promoted and miR-199a-3p attenuated neurite growth in sciatic nerve injury rats via targeting PTEN in the regulation of Akt/mTOR pathway.297

Similarly, long noncoding RNAs (lncRNAs) have been shown to respond to exercise as well, promoting cell proliferation and differentiation during tissue regeneration.355 A set of lncRNAs have been reported to play key roles in myogenesis and adult skeletal muscle regeneration.356 Amongst them, the overexpression‎ of lncRNA CYTOR, responding to exercise in both human and rodents, in mouse myogenic progenitor cells enhanced myogenic differentiation by sequestering the transcription factor Tead1, which was a regulatory mechanism of fast-twitch myogenesis in aging.357 Meanwhile, lncRNA CPhar358 and lncExACT1359 have been found to be regulated in exercised heart. Notably, lncRNA CPhar, characterized to be increased with exercise, triggered exercise-induced cardiac physiological hypertrophy via sequestering C/EBPβ and downregulating activating transcription factor 7 (ATF7), thus preventing myocardial ischemic injury-induced cardiac remodeling and dysfunction.358 Whereas lncExACT1 increased in heart failure but decreased in exercised hearts, inhibition of which induced cardiomyogenesis and protected against cardiac fibrosis and dysfunction as well.359 Dachsous cadherin-related 2 (DCHS2) had a role in the heart as a downstream effector of lncExACT1, mainly targeting Hippo/YAP signaling.359 Although evidence is still lacking to support the comprehensive functionality of most lncRNAs, the high tissue-specificity and regulation of specific facets of cellular networks have suggested that lncRNAs are superior to proteins in terms of potential, undesired toxic effects associated with their targeting360 (Fig. 6).

Fig. 6

Noncoding RNA regulating the exercise-induced regeneration. Exercise induces many noncoding RNAs in the regulation of physiological response. MiR-17-3p acts as the upstream of PTEN by inhibiting TIMP3, promoting cardiomyocyte proliferation and hypertrophy through Akt/mTOR pathway. Another two miRNAs, miR-26, and miR-16, also involve in the Akt/mTOR pathway. ADAR2 inhibits miR-34a, targeting SIRT1, CyclinD1, and Bcl2 and leading to cardiomyocyte proliferation. Exercise-induced miR-222 decreases the expression‎ of HIPK1, promoting cardiomyogenesis. Furthermore, miR-1 and miR-133 promote myogenesis via inhibiting HDAC4 and SRF, respectively. MiR-122-5p can promote angiogenesis through AGPAT1 pathway. Additionally, miR-27a-5p upregulates the expression‎ of SOST to achieve osteogenesis. Of note, miR-21 and miR-199a-3p are also regulated by exercise, which is involved in PTEN/Akt signaling pathway. While miR-135a-5p promotes neurogenesis via inhibiting IP3 pathway. Exercise also modulates the effect of lncRNA on tissue regeneration. LncRNA CYTOR can achieve myogenesis through sequestering Tead1. LncExACT1 induces pathological myocardial hypertrophy, which is downregulated by exercise. While lncRNA CPhar promotes cardiomyogenesis through decreasing ATF7 by sequestering C/EBPβ. Created with BioRender

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Potential exercise mimetics contributing to tissue regeneration

As is mentioned that exercise induces a set of physiological responses that benefit regeneration on various organs, it has gained great potential for use in patients having low exercise compliance or in those for whom regular exercise is not feasible. Consequently, exercise mimetics may have therapeutic applications across a variety of diseases. The following part reviews candidate exercise mimetics with emerging therapeutic targets and strategies for the development of exercise mimetics.

조직 재생에 기여하는 잠재적 운동 모방제
운동은 다양한 장기의 재생에 도움이 되는 일련의 생리적 반응을 유도하기 때문에 운동 순응도가 낮거나 규칙적인 운동이 불가능한 환자에게 사용할 수 있는 잠재력이 큰 것으로 알려져 있습니다. 따라서 운동 모방제는 다양한 질병에 걸쳐 치료제로 활용될 수 있습니다. 다음 부분에서는 새로운 치료 표적과 운동 모방제 개발 전략을 가진 후보 운동 모방제를 검토합니다.

Pharmaceuticals

Indeed, AMPK/SIRT1/PGC-1α pathway acts as an important role of exercise-induced physiological responses. Given it, AMPK agonists are proposed as the promising exercise mimetics.361,362,363 However, it is widely recognized that AMPK activation induces a switch of cellular metabolism from anabolic to catabolic, promoting ATP conservation by inhibiting cell growth and proliferation, which makes AMPK agonists specialize in anti-tumor therapy rather than regeneration.364,365,366,367 Nevertheless, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), one of the AMPK agonists, promotes angiogenesis in muscle by activating AMPK signaling in endothelial cells, mimicking the effects of exercise.368,369 Interestingly, though the majority of the effects of AICAR on skeletal muscles are AMPK-dependent, it may have indirect effect of AMPK activation in other organs. For example, AICAR has been suggested to increase hippocampus neuron number via activating the overexpression‎ of BDNF, improving spatial memory; however, it cannot maintain a sustained positive effect as well as running due to the poor permeability through the blood–brain barrier.370,371,372 In addition, AICAR acts as an exercise mimetic in settings of fatty liver disease, enhancing the ischemic tolerance and the regenerative capacity of fatty liver.186 Likewise, another AMPK agonist exhibiting impressive exercise mimicking capability is metformin, which is extensively used as a first-line antiglycemic drug.373 Metformin showed positive cognitive effects or increased memory function via promoting angiogenesis, AHN, and remyelination in aged or stroke rodent models.374,375,376 Besides neurogenesis, metformin also has exhibited capability of osteogenesis, inducing the similar effects on femoral BMD gains compared to plyometric exercise in ovariectomized rats.377

PPARs are proposed to interact with PGC-1α, promoting a series of exercise-induce responses. Deficiency of PPARδ has been reported to result in a reduction of satellite cell number and the regenerative capacity.378 PPARδ increased the proliferation and differentiation of myoblasts through FOXO1, whereas GW501516, a kind of synthetic PPARδ agonist, promoted the processes of myogenesis.379,380 More recently, GW501516 was also reported to limit muscle tissue damage and restores muscle tetanic contraction in mice via mimicking localized exercise-induced inflammation by upregulating Forkhead box A2.381 Notably, GW0742, another synthetic PPARδ agonist, promoted angiogenesis and cell proliferation in muscle382 and heart383 via activation of calcineurin. Similar to AICAR and metformin, GW501516 and GW0742 increased memory performance and enhanced hippocampal neurogenesis as well.370,384 Thus, a phase IIa clinical study was carried out to test T3D-959, a newly synthetic PPARδ agonist, in subjects with mild to moderate Alzheimer’s disease, which suggests that PPARδ agonists are also moving towards clinical translation.385

Angiotensin II receptor blockade, an anti-hypertensive agent, is also an impressive replacement of exercise-induced regeneration. Losartan, a classical angiotensin-receptor blockade, was reported to limit post-infarct ventricular remodeling in rats, predominantly mimicking the protective effect of exercise on the heart.386 More recently, losartan reversed allodynia, reduced muscle fibrosis, and improved muscle regeneration in a murine model of orthopedic trauma combining tibia fracture and pin fixation with muscle damage, recapitulating the exercise-induced regeneration on post-injury recovery387 (Fig. 7).

약학

실제로 AMPK/SIRT1/PGC-1α 경로는 운동으로 인한 생리적 반응의 중요한 역할을 합니다. 이에 따라 AMPK 작용제가 유망한 운동 모방제로 제안되고 있습니다.361,362,363 그러나 AMPK 활성화는 세포 대사를 동화 작용에서 이화 작용으로 전환하여 세포 성장과 증식을 억제함으로써 ATP 보존을 촉진하여 AMPK 작용제가 재생보다는 항종양 치료에 특화되어 있다는 것이 널리 알려져 있습니다.364,365,366,367 그럼에도 불구하고 AMPK 작용제 중 하나인 5- 아미노이미다졸-4- 카르복사마이드 리보뉴클레오티드(AICAR)는 내피 세포에서 AMPK 신호를 활성화하여 운동의 효과를 모방함으로써 근육의 혈관 신생을 촉진합니다.368,369 흥미롭게도 골격근에 대한 AICAR의 효과는 대부분 AMPK 의존적이지만 다른 장기에서 AMPK 활성화의 간접적인 효과를 가질 수 있습니다. 예를 들어, AICAR은 BDNF의 과발현을 활성화하여 해마 신경세포 수를 증가시켜 공간 기억력을 향상시키는 것으로 제안되었지만, 혈액 뇌 장벽을 통과하는 투과성이 낮기 때문에 달리기처럼 지속적인 긍정적 효과를 유지할 수는 없습니다.370,371,372 또한 AICAR은 지방간 질환 환경에서 운동 모방제로 작용하여 허혈성 내성과 지방간 재생 능력을 향상시키는 것으로 나타났습니다.186 마찬가지로 인상적인 운동 모방 능력을 보이는 또 다른 AMPK 작용제는 1차 항혈당제로 광범위하게 사용되는 메트포르민입니다.373 메트포르민은 노화 또는 뇌졸중 설치류 모델에서 혈관 신생, AHN 및 재수초화를 촉진하여 긍정적인 인지 효과를 나타내거나 기억 기능을 증가시켰습니다.374,375,376 메트포르민은 신경 생성 외에도 난소 절제 쥐에서 플라이오메트릭 운동과 비교하여 대퇴골 BMD 증가에 유사한 효과를 유도하는 골 형성 능력도 입증했습니다.377

PPAR은 PGC-1α와 상호 작용하여 일련의 운동 유도 반응을 촉진하는 것으로 알려져 있습니다. PPARδ의 결핍은 위성 세포 수와 재생 능력의 감소를 초래하는 것으로 보고되었습니다.378 PPARδ는 FOXO1을 통해 근아 세포의 증식과 분화를 증가시키는 반면, 합성 PPARδ 작용제의 일종인 GW501516은 근육 형성 과정을 촉진했습니다.379,380 최근에는 GW501516이 포크헤드 박스 A2를 상향 조절하여 국소 운동 유발 염증을 모방함으로써 생쥐의 근육 조직 손상을 제한하고 근육 태탄성 수축을 회복시키는 것으로 보고되었습니다.381 특히 또 다른 합성 PPARδ 작용제인 GW0742는 칼시뉴린의 활성화를 통해 근육382 및 심장383에서 혈관 신생 및 세포 증식을 촉진했습니다.

AICAR 및 메트포르민과 유사하게 GW501516 및 GW0742는 기억력을 향상시키고 해마 신경 생성도 강화했습니다.370,384 따라서 경증에서 중등도 알츠하이머병 환자를 대상으로 새로운 합성 PPARδ 작용제인 T3D-959를 테스트하는 임상 2a상 연구가 진행되어 PPARδ 작용제 또한 임상 전환을 향해 나아가고 있음을 시사하고 있습니다.385

항고혈압제인 안지오텐신 II 수용체 차단제 역시 운동으로 인한 재생을 대체할 수 있는 인상적인 약제입니다. 고전적인 안지오텐신 수용체 차단제인 로사르탄은 쥐에서 경색 후 심실 리모델링을 제한하여 주로 운동의 심장 보호 효과를 모방하는 것으로 보고되었습니다.386 최근에는 경골 골절과 핀 고정을 동반한 정형외과 외상 쥐 모델에서 이질통을 역전시키고 근육 섬유화를 줄이며 근육 재생을 개선하여 부상 후 회복에 운동 유발 재생을 요약했습니다387 (그림 7).

Fig. 7

Emerging pharmaceuticals mimicking exercise-induced tissue regeneration. AMPK/SIRT1/PGC-1α/PPARδ pathway has been selected as an important intervention of exercise-induced physiological responses. AICAR, metformin, GW501516, and GW0742, used to mimic exercise-induced physiological responses, demonstrate the ability to promote damaged tissue repair. Additionally, losartan is used to promote muscle regeneration. Created with BioRender

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Natural molecular mediators

As mentioned above, the organism will release various natural molecular mediators involved in signaling pathways that promote regeneration during exercise. The regulatory mechanisms of these biomolecules are being understood by a wide range of researchers, which allows biosynthetic agents or genetic drugs to mimic the effects of exercise as well.

Irisin, a novel myokine, cleaved from membrane precursor fibronectin type III domain-containing 5 (FNDC5) in response to exercise, and acts as a linkage between muscles and other tissues.388 Besides inducing browning of white adipose tissue, irisin was discovered to promote proliferation and differentiation of osteoblasts through activating the p38 and ERK signaling.389,390 In the meantime, recombinant irisin positively regulated osteoblast differentiation under simulated microgravity via the overexpression‎ of β-catenin, successfully providing a prevention strategy for bone loss and muscle atrophy induced by microgravity.391 Interestingly, irisin was also reported to bind to the proteins of the αV class of integrins, increasing production of SOST involved in bone resorption by increasing osteoclasts activity, which implied the two-sided effects of irisin on the therapeutic potential of skeletal remodeling.392 In terms of neuroprotection, circulating irisin crossed the blood-brain barrier and elevated BDNF level in the hippocampus, thereby promoting neurogenesis, enhancing synaptic plasticity, and modulating inflammation, which was demonstrated in models of neurodegenerative disease and cerebral ischemia.393,394,395 Furthermore, a recent study showed that recombinant adenovirus containing the irisin sequence improved burn-related neuropathy by ameliorating neuroinflammation-induced neuronal apoptosis, which demonstrated the protective effect of irisin on the PNS as well.396 Therefore, the therapeutic mechanism of irisin is not fully understood but has strong potential.

Adiponectin, one of the emerging adipokines, is also modulated by exercise, thus exerting a regenerative effect. Chronic exercise training imposed to rodents increased circulating adiponectin levels and AdipoR1 (adiponectin specific muscle receptor) expression‎.397,398 Thus, adiponectin was found to be responsible for the exercise-induced restoration of satellite cell mobilization, regenerative capacity in aged mice via the AMPK/SIRT1/PGC-1α axis.399 Moreover, adiponectin is capable of crossing the blood-brain barrier and affecting the CNS. Adiponectin mimicked exercise-induced effects in stress-elicited depression mice by retaining the normal proliferation of neural progenitors and dendritic morphology of neurons in the hippocampal dentate gyrus.400 In addition, AdipoRon (adiponectin receptor agonist), which mimicked the effects of running, rescued impaired cognitive function by improving hippocampal neurogenesis via adiponectin-Notch pathway.401 Similarly, AdipoRon treatment confirmed the exercise-induced hippocampal neuroplasticity in diabetic mice as well, which provides another promising candidate exercise mimetics.402,403

There are a set of immunomodulatory cytokines secreted into the circulation during exercise, such as interleukin-6 (IL-6) and IL-15, which are also integrated into the list of candidate exercise mimetics. IL-6 has been found to be synthesized and secreted into circulating by skeletal muscle during exercise, activating PI3K/Akt signaling, MAPK signaling and AMPK signaling in targeting cells.404,405,406 IL-6 was shown to promote proliferation of post-natal murine neural stem cell numbers.407 Thus, administration of recombinant IL-6 in a low-dose pulsatile strategy might directly modulate Schwann and nerve cells as a regenerative response to exercise in diabetic peripheral neuropathy.408 Notably, tocilizumab, one of the IL-6 receptor antibodies, has been used to treat some forms of arthritis.409 The side effect, such as blocking of exercise-mediated loss of visceral adipose tissue mass, has been confirmed recently.410,411 Whether the application of IL-6 receptor antibodies will block exercise-induced regenerative capacity is also a topic worthy of further investigation. While IL-15 is also a myokine of the IL-2 family responding to exercise.412 IL-15 has been reported to have local effects on skeletal muscles, such as promoting myoblast differentiation.413,414 Furthermore, exercise-mediated improvements in the healing of aged skin depend upon circulating IL-15. Exercise-mimicking recombinant IL-15 directly enhanced the growth of the aged mouse fibroblasts and keratinocytes, promoting impaired wound healing via activation of signal transducer and activator of transcription 3 signaling pathway, even though it was barely scarless regeneration415 (Fig. 8).

천연 분자 매개체

위에서 언급했듯이 신체는 운동 중에 재생을 촉진하는 신호 전달 경로에 관여하는 다양한 천연 분자 매개체를 방출합니다. 이러한 생체 분자의 조절 메커니즘은 광범위한 연구자들에 의해 이해되고 있으며, 이를 통해 생합성제나 유전자 약물도 운동의 효과를 모방할 수 있습니다.

새로운 마이오카인인 이리신은

운동에 반응하여 막 전구체인 피브로넥틴 3형 도메인 함유 5(FNDC5)에서 절단되어

근육과 다른 조직을 연결하는 역할을 합니다.388

이리신은 백색 지방 조직의 갈색화를 유도하는 것 외에도

p38 및 ERK 신호를 활성화하여 조골세포의 증식과 분화를 촉진하는 것으로 밝혀졌습니다.389,390

한편, 재조합 이리신은 β-카테닌의 과발현을 통해 모의 미세 중력 하에서 조골세포 분화를 긍정적으로 조절하여 미세 중력에 의해 유도된 골 손실과 근육 위축을 예방하는 전략을 성공적으로 제공했습니다.391 흥미롭게도 이리신은 αV 계열의 통합인자 단백질에 결합하여 파골세포 활동을 증가시켜 골 흡수에 관련된 SOST의 생산을 증가시키는 것으로 보고되었으며 이는 이리신의 양면 효과가 골격 리모델링의 치료 잠재력을 시사하는 것으로 나타났습니다.392 신경 보호 측면에서 순환하는 이리신은 혈액-뇌 장벽을 통과하여 해마에서 BDNF 수준을 높여 신경 생성을 촉진하고 시냅스 가소성을 강화하며 염증을 조절하며, 이는 신경 퇴행성 질환 및 뇌 허혈 모델에서 입증되었습니다.393,394,395 또한, 최근 연구에 따르면 이리신 서열을 포함하는 재조합 아데노 바이러스가 신경염증으로 인한 신경 세포 사멸을 개선하여 화상 관련 신경 병증을 개선하여 이리신의 PNS 보호 효과도 입증했습니다.396 따라서 이리신의 치료 메커니즘은 완전히 이해되지는 않았지만 강력한 잠재력을 가지고 있습니다.

새롭게 떠오르는 아디포카인 중 하나인

아디포넥틴도 운동에 의해 조절되어 재생 효과를 발휘합니다.

설치류에 만성 운동 훈련을 실시하면 순환하는 아디포넥틴 수치와 아디포넥틴 특정 근육 수용체(AdipoR1) 발현이 증가했습니다.397,398 따라서 아디포넥틴은 운동으로 인한 위성 세포 이동의 회복, AMPK/SIRT1/PGC-1α 축을 통한 노화된 쥐의 재생 능력을 담당하는 것으로 밝혀졌습니다.399 또한 아디포넥틴은 혈액 뇌 장벽을 통과하여 CNS에 영향을 미칠 수 있는 것으로 밝혀졌습니다.

아디포넥틴은 스트레스 유발 우울증 마우스에서 신경 전구세포의 정상적인 증식과 해마 상아상교에서 신경세포의 수지상 형태를 유지함으로써 운동으로 인한 효과를 모방했습니다.400 또한 달리기의 효과를 모방한 아디포론(아디포넥틴 수용체 작용제)은 아디포넥틴-노치 경로를 통해 해마 신경 생성을 개선하여 손상된 인지 기능을 회복시켰습니다.401 마찬가지로 아디포론 치료는 당뇨병 마우스에서도 운동에 의한 해마 신경 가소성을 확인하여 또 다른 유망한 운동 모방제 후보를 제공합니다.402,403

인터루킨-6(IL-6) 및 IL-15와 같이

운동 중에 순환계로 분비되는 일련의 면역 조절 사이토카인도

운동 모방 물질 후보 목록에 포함되어 있습니다.

IL-6는 운동 중 골격근에서 합성되어 순환계로 분비되어 표적 세포에서 PI3K/Akt 신호, MAPK 신호 및 AMPK 신호를 활성화하는 것으로 밝혀졌습니다.404,405,406

IL-6는 출생 후 쥐 신경 줄기세포 수의 증식을 촉진하는 것으로 나타났습니다.407 따라서 저용량 박동성 전략으로 재조합 IL-6를 투여하면 당뇨병 말초 신경병증의 운동 재생 반응으로서 슈반 및 신경 세포를 직접 조절할 수 있습니다.408 특히 IL-6 수용체 항체 중 하나인 토실리주맙은 일부 형태의 관절염 치료에 사용되었습니다.409 운동에 의한 내장 지방 조직의 손실 차단과 같은 부작용이 최근에 확인되었습니다.410,411 IL-6 수용체 항체의 적용이 운동에 의한 재생 능력을 차단하는지 여부도 추가 연구할 가치가 있는 주제입니다. IL-15도 운동에 반응하는 IL-2 계열의 마이오카인입니다.412 IL-15는 근아세포 분화를 촉진하는 등 골격근에 국소적인 영향을 미치는 것으로 보고되었습니다.413,414 또한 운동을 매개로 한 노화된 피부의 치유 개선은 순환하는 IL-15에 따라 달라집니다. 운동 모방 재조합 IL-15는 노화된 마우스 섬유아세포와 각질 세포의 성장을 직접적으로 향상시켜 신호 전달체와 전사 3 신호 경로의 활성화제를 통해 손상된 상처 치유를 촉진하여 흉터가 거의 없는 재생임에도 불구하고415 (그림 8).

Fig. 8

Natural molecular mediators. A set of exerkines are considered as candidate exercise mimetics, including irisin, adiponectin and interleukin, which can be used as gene therapy. These emerging target molecules provide new insights into the mechanisms of injured tissue regeneration and facilitate the efficiency of clinical translation. Created with BioRender

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Discussion and perspective

Application of exercise intervention under aging condition

With the progress of society, the average human life expectancy has increased significantly. In parallel with longer lifespan, aging-specific health problem have emerged, which makes a growing global burden. Although it is brought to light that aging can not to be abolished, it is still expected to be able to attenuate the process and greatly ameliorate its effects, which implies the ultimate goal is not only longer lifespan, but also a better quality of life.416 Indeed, besides trauma and inflammation, aging is a vital process in the lifespan, whose essence is replicative cellular senescence.417 Senescent cells accumulate at sites of age-related pathologies and have an impact on the normal physiology of the tissues, causing a progressive functional deterioration.418 Exercise training is considered as a promising regenerative intervention for aged tissues, contributing to prevention and management of the challenging chronic diseases faced by elderly population.

Dementia is characterized by impairment of cognitive abilities and memory. Alzheimer’s disease (AD), a main and common type of dementia, is probably identified as age-related impairment of AHN.143 It has been reported that exercise not only reduces the risk of developing AD in aged population, but also improves the cognitive function of individuals with mild cognitive impairment and AD.419 Increasing evidence suggests that a variety of bioactive substances induced by exercise exert neuroprotective effects in mouse models via restoration of AHN and regulation of synaptic plasticity as well.420,421 In addition, numerous studies have shown that exercise can improve the poor prognosis of other age-related neurodegeneration via promoting neuronal survival and plasticity, or neurogenesis.422 Interestingly, endurance exercise has been reported to enhance the secretion of an enzyme, called glycosylphosphatidylinositol-specific phospholipase D1, derived from liver, ameliorating impaired neurogenesis and cognition in the aged hippocampus of mice.423 It is a new approach to explore the influence of other organs on the aged brain, providing new targets for the treatment of neurodegenerative diseases.

The level of bone loss increases with age, leading to osteoporosis in the elderly, particularly postmenopausal woman, which increases risk of fractures. Exercise training is considered as an effective method to stimulate bone osteogenesis in osteoporotic patients. As is mentioned, bone is a force-receptive organ, which needs to achieve sufficient mechanical intensity to effectively trigger the response of osteogenesis. As a result, not all types of exercise have the same positive effect on BMD. High intensity aerobic or resistance exercises are confirmed to be more effective in promoting the increase of BMD.424,425 In addition, several meta-analyses have shown that exercise appears extremely site-specific, increasing BMD only in the stimulated body regions.426,427 Thus, more composite exercises of diverse patterns and intensities need to be explored in order to more effective bone regeneration in whole body of aging adults.

Sarcopenia, the loss of skeletal muscle mass and strength, is an inevitable event during the aging process, which reduces physical capacity and enhances the problems associated with disabilities.428 Capelli et al.429 indicated that decay of maximal aerobic power and anaerobic capacity occurred with aging in cycling athletes, confirm‎ing age-related loss of muscle mass. Accumulating evidence supports that exercise training represents an effective intervention strategy to reduce or even reverse age-related loss of muscle mass as well.430 A meta-analysis, including 1,328 adults, demonstrated that resistance exercise training was effective in eliciting gains in lean body mass among the older people, particularly if they performed higher volume programs.431 Thus, as an effect of the independent exercise regimes on muscle mass, resistance exercise programs seem to be mostly effective in increasing muscle strength in sarcopenic frail elderly people.432,433 In regard of the cellular level, both resistance and endurance exercise training have shown to increase the number of satellite cells for regeneration in old animals and humans.434,435,436,437 The key role for muscle regeneration may be the intensity and frequency of exercise stimulation, however, the specific mechanisms responsible for re-trigger of growth capacity by exercise are not of comprehensive recognition yet.

토론 및 관점

노화 상태에서의 운동 개입 적용

사회가 발전함에 따라 인간의 평균 수명은 크게 늘어났습니다. 수명의 연장과 함께 노화에 따른 건강 문제가 대두되어 전 세계적으로 부담이 커지고 있습니다. 노화를 없앨 수는 없지만 그 과정을 완화하고 그 영향을 크게 개선할 수 있을 것으로 기대되며, 이는 궁극적인 목표가 수명 연장뿐만 아니라 삶의 질 향상에 있음을 의미합니다.416 실제로 노화는 외상과 염증 외에도 수명에 있어 중요한 과정이며, 그 본질은 복제 세포 노화입니다.417 노화 세포는 노화와 관련된 병리 부위에 축적되어 조직의 정상적인 생리에 영향을 미치고 점진적인 기능 저하를 유발합니다.418 운동 훈련은 노화 조직에 대한 유망한 재생 개입으로 간주되며 노인 인구가 직면하는 어려운 만성 질환의 예방 및 관리에 기여합니다.

치매는 인지 능력과 기억력 손상이 특징입니다. 치매의 주요하고 흔한 유형인 알츠하이머병(AD)은 아마도 AHN의 연령 관련 손상으로 확인되고 있습니다.143 운동은 고령 인구의 AD 발병 위험을 감소시킬 뿐만 아니라 경도인지장애 및 AD 환자의 인지 기능을 개선하는 것으로 보고되었습니다.419 운동으로 유도된 다양한 생리 활성 물질이 마우스 모델에서 AHN의 회복과 시냅스 가소성 조절을 통해 신경 보호 효과를 발휘한다는 증거가 증가하고 있습니다.420,421 또한, 수많은 연구에 따르면 운동은 신경세포의 생존과 가소성 또는 신경 생성을 촉진하여 다른 노화 관련 신경 퇴행의 나쁜 예후를 개선할 수 있는 것으로 나타났습니다.422 흥미롭게도 지구력 운동은 간에서 유래한 글리코실포스파티딜이노시톨 특이적 포스포리파제 D1이라는 효소의 분비를 촉진하여 생쥐의 노화된 해마에서 손상된 신경 발생과 인지를 개선하는 것으로 보고되었습니다.423 이는 노화된 뇌에 대한 다른 기관의 영향을 탐구하는 새로운 접근법으로, 신경 퇴행성 질환의 치료를 위한 새로운 표적을 제공합니다.

나이가 들수록 골 손실이 증가하여 노인, 특히 폐경 후 여성의 골다공증으로 이어져 골절 위험이 증가합니다. 운동 훈련은 골다공증 환자의 뼈 골 형성을 자극하는 효과적인 방법으로 간주됩니다. 앞서 언급했듯이 뼈는 힘을 받아들이는 기관으로, 골 형성의 반응을 효과적으로 유발하려면 충분한 기계적 강도를 달성해야 합니다. 따라서 모든 유형의 운동이 BMD에 동일한 긍정적인 영향을 미치는 것은 아닙니다. 고강도 유산소 운동이나 저항 운동이 BMD 증가를 촉진하는 데 더 효과적인 것으로 확인되었습니다.424,425 또한 여러 메타 분석에 따르면 운동은 자극을 받은 신체 부위에서만 BMD가 증가하는 부위 특이적인 것으로 나타났습니다.426,427 따라서 노화 성인의 전신 골 재생을 보다 효과적으로 촉진하기 위해서는 다양한 패턴과 강도의 복합 운동이 더 많이 연구될 필요가 있습니다.

골격근량과 근력의 감소인 근감소증은 노화 과정에서 피할 수 없는 현상으로 신체 능력을 감소시키고 장애와 관련된 문제를 증가시킵니다.428 Capelli등429 은 사이클 선수의 노화와 함께 최대 유산소 능력과 무산소 능력의 감소가 발생하여 노화와 관련된 근육량 감소가 확인되었다고 지적했습니다. 축적된 증거는 운동 훈련이 연령과 관련된 근육량 손실을 줄이거나 심지어 역전시키는 효과적인 중재 전략임을 뒷받침합니다.430 성인 1,328명을 대상으로 한 메타 분석에 따르면 저항 운동 훈련은 특히 고강도 프로그램을 수행한 경우 노인의 제지방량 증가를 유도하는 데 효과적이었습니다.431 따라서 근육량에 대한 독립적인 운동 요법의 효과로서 저항 운동 프로그램은 대부분 근감소증 허약 노인의 근력 증가에 효과적인 것으로 보입니다.432,433 세포 수준에서 볼 때, 저항성 및 지구력 운동 훈련 모두 늙은 동물과 인간에서 재생을 위한 위성 세포의 수를 증가시키는 것으로 나타났습니다.434,435,436,437 근육 재생의 핵심 역할은 운동 자극의 강도와 빈도일 수 있지만 운동으로 성장 능력을 다시 유발하는 구체적인 메커니즘은 아직 종합적으로 인식되지 않고 있습니다.

Limitation and prospects of exercise intervention

Although remarkable progress has been made in the treatment of exercise interventions over the past few decades (Table 1), the side effects of over exercise are also being recognized. It is common to visualize that excessive-exercise or inappropriate exercise leads to sport-related injuries, ranging from the ankle and the knee, to the face and even the brain, which has ruined the careers of most athletes.438,439,440,441 Notably, chronic excessive exercise might adversely impact cardiovascular health. The increased incidence of atrial fibrillation seen in endurance athletes is one of the best documented cardiac maladaptations, which is related to exercise-induced changes in autonomic tone alongside the development of an arrhythmogenic atrial substrate.442 Myocardial fibrosis and coronary artery calcification have also been detected in ultra-endurance races.443,444 In addition, the marked suppression of growth factors and hormones, including testosterone, IGF-1, and leptin, after ultra-endurance exercise has also reported, which is strongly associated with the magnitude of the energy deficit.445 It has been realized that excessive exercise leads to immune imbalance and decrease in reactive oxygen species scavenging capacity, which has deleterious effects on health as well.446 Fortunately, with a better understanding of the adaptive responses of the organism to exercise gained, it has been found that we all carry our own “endogenous medicine box”. We have the opportunity to take the most applicable pills from the box to target a variety of different diseases. Thus, how to explore and make good use of the body’s own endogenous health resources, especially how to develop personalized rehabilitation exercise prescriptions for different diseases and different patients, has attracted more and more researchers to explore this field.

Table 1 Clinical trials related to exercise intervention in diverse diseases

Full size table

As a matter of fact, the knowledge of the adaptive responses to exercise is still only the tip of the iceberg. There are still three major points in the current researches on exercise for regeneration requiring further exploration. Firstly, the organism responds differently to diverse exercise patterns and intensities with great individual variability, resulting in instability and poor reproducibility of the exercise test. Therefore, the design of a rational exercise intervention is helpful to investigate the mechanisms of exercise regeneration, which is more effectively applied in clinical treatment further. Secondly, although the role of exercise for tissue regeneration undoubtedly brings new ideas and strategies, exercise mimetics need in-depth exploration. Notably, exercise mimetics may have utility across a wide range of human disorders, which is a gift for patients who are subjectively or objectively unable to achieve exercise benefits. However, as individual variability in exercise, exercise mimetics are not going to work as a universal panacea for divergent disorders but are more likely to be most effective for specific disorders, or even subtypes of such disorders. Thus, exploration of multi-target exercise mimetics is a key step in broadening the range of applications and improving the value of clinical translation. Thirdly, regeneration is indeed an anti-aging remedy, but it also often goes hand in hand with tumors. Whether exercise mimetics have a carcinogenic risk while promoting cell proliferation deserves more research to prove, which means a higher demand on the administration and dose of the drugs.

Beyond any doubt, exercise-induced regenerative medicine is an emerging and promising discipline. Currently, a variety of signaling pathways and related novel biomolecules have been identified in exercise adaptive regeneration, exhibiting more potential perspectives for disease prevention and treatment.

References

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