Re: 카르니틴.. 효과와 부작용 2022 리뷰

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스페르미딘, 크레아틴, 베타 알라닌, 아르기닌, 시트룰린, 글루타민, BCAA, 타우린, 티로신, 트립토판, 오르니틴, 테아닌, GABA, 아세틸 L-카르니틴, DL-페닐알라닌, 5-HTP, SAMe, N-아세틸 시스테인, DMAE, 아그마틴, 포스파티딜세린, 이노시톨, 콜린 등

• Review
• Open access
• Published: 21 September 2020

The bright and the dark sides of L-carnitine supplementation: a systematic review

• Angelika K. Sawicka, 
• Gianluca Renzi & 
• Robert A. Olek 

Journal of the International Society of Sports Nutrition volume 17, Article number: 49 (2020) Cite this article

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Abstract

Background

L-carnitine (LC) is used as a supplement by recreationally-active, competitive and highly trained athletes. This systematic review aims to eval‎uate the effect of prolonged LC supplementation on metabolism and metabolic modifications.

Methods

A literature search was conducted in the MEDLINE (via PubMed) and Web of Science databases from the inception up February 2020. Eligibility criteria included studies on healthy human subjects, treated for at least 12 weeks with LC administered orally, with no drugs or any other multi-ingredient supplements co-ingestion.

Results

The initial search retrieved 1024 articles, and a total of 11 studies were finally included after applying inclusion and exclusion criteria. All the selected studies were conducted with healthy human subjects, with supplemented dose ranging from 1 g to 4 g per day for either 12 or 24 weeks. LC supplementation, in combination with carbohydrates (CHO) effectively elevated total carnitine content in skeletal muscle.

Twenty-four-weeks of LC supplementation did not affect muscle strength in healthy aged women, but significantly increased muscle mass, improved physical effort tolerance and cognitive function in centenarians. LC supplementation was also noted to induce an increase of fasting plasma trimethylamine-N-oxide (TMAO) levels, which was not associated with modification of determined inflammatory nor oxidative stress markers.

Conclusion

Prolonged LC supplementation in specific conditions may affect physical performance. On the other hand, LC supplementation elevates fasting plasma TMAO, compound supposed to be pro-atherogenic. Therefore, additional studies focusing on long-term supplementation and its longitudinal effect on the cardiovascular system are needed.

배경

L-카르니틴(LC)은

레크리에이션 활동, 경쟁 및 고강도 훈련을 하는 운동선수들이 보충제로 사용합니다.

이 체계적 문헌 고찰은

장기적인 LC 보충이 대사 및 대사 변화에 미치는 영향을 평가하는 것을 목표로 합니다.

방법

MEDLINE(PubMed를 통해) 및 Web of Science 데이터베이스에서 2020년 2월까지의 문헌 검색이 수행되었습니다.

적격 기준에는 건강한 인간 대상자,

LC를 경구 투여로 최소 12주 동안 치료받은 연구, 약물이나 기타 다성분 보충제와의 병용 투여가 없는 연구가 포함되었습니다.

결과

초기 검색에서 1,024편의 논문이 검색되었으며, 포함 및 제외 기준을 적용한 후 최종적으로 11편의 연구가 포함되었습니다.

선정된 모든 연구는

건강한 인간 대상자를 대상으로 진행되었으며,

보충 용량은 하루 1g에서 4g 사이로 12주 또는 24주간 투여되었습니다.

LC 보충은

탄수화물(CHO)과 결합하여

골격근의 총 카르니틴 함량을 유의미하게 증가시켰습니다.

24주간의 LC(L-카르니틴) 보충제 섭취는

건강한 노년 여성의 근력에는 영향을 미치지 않았으나,

100세인(centenarians)의 근육량 증가, 신체 활동 내성 및 인지 기능 개선에 유의미한 효과를 보였습니다.

LC 보충제 섭취는 또한

공복 혈장 트리메틸아민-N-옥사이드(TMAO) 수치를 증가시키는 것으로 나타났으나,

이는 염증 또는 산화 스트레스 표지자의 변화와 관련이 없었습니다.

결론

특정 조건 하에서 장기적인 LC 보충은

신체 성능에 영향을 미칠 수 있습니다.

반면,

LC 보충은 동맥경화 촉진 물질로 알려진 공복 혈장 TMAO 수치를 증가시킵니다.

따라서 장기 보충과 심혈관 시스템에 대한 장기적 효과를 평가하는 추가 연구가 필요합니다.

Background

The main function of L-carnitine (LC) is the transport of long-chain fatty acids into the mitochondrial matrix for their conversion in energy, via β-oxidation process [1]. Moreover, LC by the reaction with acetyl-CoA and maintaining the acetyl-CoA/CoA ratio in the cell regulates pyruvate dehydrogenase activity [2]. LC also plays an important role in the regulation of metabolic pathways involved in skeletal muscle protein balance: proteolysis and protein synthesis [3]. Furthermore, LC acts as anti-oxidant and anti-inflammatory compound [3]; thus, it may attenuate the exercise-induced muscle damage.

The opinion that LC supplementation does not change metabolism is based mostly on short-term supplementation protocols [4]. Recent studies demonstrate that prolonged supplementation, especially in combination with carbohydrates (CHO), may increase muscle total carnitine (TC) content in skeletal muscle [5,6,7]. Therefore, LC supplementation in specific conditions may affect physical performance. On the other hand, LC has been proposed as the red meat nutrient responsible for atherosclerosis promotion [8]. As a potential link between red meat consumption and the increasing risk of cardiovascular disease, trimethylamine-N-oxide (TMAO) has been indicated [8]. Since LC is still used by the athletes [9, 10], the aim of this systematic review is to eval‎uate the effect of prolonged LC supplementation on metabolism/metabolic changes in healthy human subjects.

Methods

배경

L-카르니틴(LC)의 주요 기능은

장쇄 지방산을 미토콘드리아 매트릭스로 운반하여

β-산화 과정을 통해 에너지로 전환하는 것입니다 [1].

또한

LC는 아세틸-CoA와의 반응을 통해

세포 내 아세틸-CoA/CoA 비율을 유지함으로써

피루vate dehydrogenase 활성을 조절합니다 [2].

LC는 골격근 단백질 균형에 관여하는 대사 경로 조절에도 중요한 역할을 합니다:

단백질 분해와 단백질 합성 [3]. 또한 LC는 항산화 및 항염증 물질로 작용합니다 [3];

따라서 운동으로 인한 근육 손상을 완화할 수 있습니다.

LC 보충이 대사 변화를 일으키지 않는다는 주장은

주로 단기 보충 프로토콜에 기반을 두고 있습니다 [4].

최근 연구들은 장기 보충,

특히 탄수화물(CHO)과 결합한 경우

골격근의 총 카르니틴(TC) 함량을 증가시킬 수 있음을 보여줍니다 [5,6,7].

따라서

특정 조건에서 LC 보충은 신체 성능에 영향을 미칠 수 있습니다.

반면,

LC는 동맥경화 촉진에 기여하는 적색 육류의 영양소로 제안되었습니다 [8].

적색 육류 섭취와 심혈관 질환 위험 증가 사이의 잠재적 연관성으로,

트리메틸아민-N-옥사이드(TMAO)가 지목되었습니다 [8].

LC는 여전히 운동선수들에 의해 사용되고 있습니다[9, 10].

따라서

이 체계적 문헌 고찰의 목적은

건강한 인간 대상에서 장기적인 LC 보충이 대사/대사 변화에 미치는 영향을 평가하는 것입니다.

Eligibility criteria

The PICOS strategy was defined as follows: “P” (participants) human subjects, “I” (interventions) oral LC treatment, “C” (comparisons) between supplementation and placebo, supplementation and control, or pre- and post- supplementation, “O” (outcomes) muscle variables, and “S” (study design) randomized controlled trials, non-randomized controlled trials, non-randomized non-controlled trials.

Studies with the following criteria were excluded: described in languages other than English, articles without full-text availability, reviews and case reports. Subsequently, the following eligibility criteria were applied: a) healthy human subjects; b) supplementation at least for 12 weeks; c) oral LC administration; d) no drugs co-ingestion; e) no multi-ingredients supplementation.

Information sources and search

The literature was explored using the MEDLINE (via PubMed) and Web of Science databases, including all articles published from the inception up February 2020. The search was conducted using the terms: “carnitine supplementation” or “carnitine treatment” in combination with “exercise”, “training”, “athletic performance”, “muscle strength”, “muscle fatigue”, “muscle damage”, “muscle recovery”, “muscle synthesis” or “proteolysis”.

Study selection

Firstly, studies were assessed by title verification between databases (duplicates were removed). The second assessment performed by abstracts analysis, excluded studies in a language other than English, studies with lack of full text, reviews, case reports, animal studies and in-vitro studies. The last step was performed by analysis of full manuscripts based on the described above eligibility criteria.

Data collection process

The following information was compiled for each study: authors, year of publication, type of study, length of supplementation, a dose of supplementation and main effect. Lastly, the thematic analysis was carried out, to synthesize and interpret all the data that appeared from the included publications. The process of selecting papers, data collection as well as the quality assessment was performed independently by two authors (A.S., G.R.), and all disagreements were resolved by the discussion with the third author (R.O).

Results

Study selection

By the above-described search strategy, 1295 publications were identified. After the first selection, adjusted by duplicates, persisted 1024 articles. Of these, 794 were excluded after abstracts screening and identified articles in languages other than English, lack of full text or being review articles, case reports, animal or in-vitro studies. The full texts of 230 articles were screened by eligibility criteria. Finally, to the qualitative analysis were accepted 11 studies performed on healthy human subjects, treated for at least 12 weeks with LC administered orally, with no drugs or any other multi-ingredient supplements co-ingestion (Fig. 1).

연구 선정: 위에 설명된 검색 전략을 통해 1295개의 출판물이 식별되었습니다. 1차 선별 후 중복을 제거하자 1024개의 논문이 남았습니다. 이 중 초록 심사 후 영어 외 다른 언어로 작성되었거나, 전문(full text)이 없거나, 리뷰 논문, 증례 보고서, 동물 또는 시험관 내(in-vitro) 연구라는 이유로 794개가 제외되었습니다. 나머지 230개 논문의 전문을 적격성 기준에 따라 심사했습니다. 최종적으로, 질적 분석을 위해 건강한 인간 피험자를 대상으로 경구 투여된 LC(L-카르니틴)로 최소 12주 동안 치료했으며, 다른 약물이나 다성분 보충제를 함께 섭취하지 않은 11개 연구가 채택되었습니다 (그림 1).

Fig. 1

Flowchart on the search and selection of articles included in the review

Full size image

Description of the included studies

Table 1 provides details and results of the 11 studies reviewed. Selected studies were published between 2002 and 2020. In the selected studies, participants were supplemented in a dose ranging from 1 g to 4,5 g per day for either 12 or 24 weeks, mostly by L-carnitine-L-tartrate (LCLT). In three studies, supplementations were combined with carbohydrates (CHO) [5,6,7], and in one with L-leucine [18].

Table 1 Summary and results of the studies reviewed examining the LC supplementation

StudiesParticipants characteristicsStudy designSupplementation dose and periodMain effect

[11]	Moderately trained male subjects (n = 7) age 23–25	NRNC	4 g LC/day for 3 months	Increase of TC plasma concentration after the supplementation; No change in muscle TC concentration, mitochondrial enzymes activity, physical performance and muscle fiber composition
[12]	Male vegetarians (n = 16) and omnivores (C) (n = 8) age 18–40	NRC	2 g LCLT /day for 12 weeks	Increase of TC plasma concentration after the supplementation and muscle TC concentration only in vegetarians; No change in physical performance and muscle metabolism either in omnivores or vegetarians.
[13]	Middle aged untrained male subjects (S n = 12; P n = 12) age not reported (both groups involved in endurance training; 3x/week)	RC	2 g LCLT /day for 12 weeks	Increase of TC plasma concentration after the supplementation; Plasma triacylglycerols and free fatty acids not affected by training or supplementation; Training resulted in an increase in the mRNA expression‎ of genes coding proteins involved in long chain fatty acid transport in white blood cells, LC supplementation enhanced the effect on gene expression‎
[6]	Non-vegetarian, male recreational athletes (S n = 6; P n = 6) age 28 ± 2 (S); 25 ± 2 (P)	RC	2 g LCLT + 80 g CHO /day for 12 weeks	Increase in muscle TC concentration after LC supplementation; Upregulation of seventy-three genes relating to fuel metabolism in LC vs. control; Higher exercise energy expenditure after LC supplementation; No change in carnitine palmitolytransferase 1 activity; Body mass and whole-body fat mass increased in control, but did not change in LC supplemented
[5]	Non-smoking, non-vegetarian recreational athletes (S n = 7; P n = 7) age 26 ± 2	RC	2 g LCLT + 80 g CHO /day for 24 weeks	Increase in muscle TC concentration after LC supplementation; Lower muscle glycogen utilization during low intensity exercise, lower lactate production during high intensity exercise, higher work output during a 30 min ‘all-out’ exercise performance test in LC supplemented group;
[7]	Healthy, non-vegetarian, untrained males (S n = 7; P n = 7) age 23 ± 2 (both groups involved in HIIT; 3x/week)	RC	2.25 g LCLT + 80 g CHO /day for 24 weeks	Muscle TC concentration tend to increase after LC supplementation (p = 0.06 vs. pre-supplementation); Skeletal muscle adaptations to training not augmented by elevated muscle carnitine availability;
[14]	Centenarians (S n = 27; P n = 27) age 100–106	RC	2 g LC/day for 24 weeks	Increase of TC plasma concentration after the supplementation; Fat mass reduction, muscle mass elevation, physical effort tolerance and cognitive function improvement in LC supplemented group
[15]	Healthy women (S n = 11; P n = 9) age 65–70	RC	1.5 g LCLT /day for 24 weeks	Increase of free carnitine plasma concentration after the supplementation; No changes in body composition, skeletal muscle strength and IGF-1 after LC supplementation
[16]	Healthy women (S n = 11; P n = 9) age 65–70	RC	1.5 g LCLT /day for 24 weeks	Increase of plasma TMAO concentration after the supplementation; No changes in serum C-reactive protein, interleukin-6, tumor necrosis factor-α, L-selectin, P-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and lipid profile after LC supplementation
[17]	Healthy women (S n = 11; P n = 9) age 65–70	RC	1.5 g LCLT /day for 24 weeks	No changes in plasma GBB or serum ox-LDL, myeloperoxidase, protein carbonyls, homocysteine, and uric acid concentrations
[18]	Healthy aged women (S n = 12; P n = 13; C n = 12) age 67 ± 3 (all groups involved in resistance training 3x/week)	RC	1 g LCLT + 3 g L-leucine/day for 24 weeks	Increase of plasma TMAO concentration after the supplementation; Increase of D-loop methylation in platelets of LC supplemented

1. Groups: C control; S supplemented; P placebo; Study design: RC randomized controlled; NRC non-randomized controlled; NRNC non-randomized non-controlled; LCLT L-carnitine-L-tartrate; HIIT high-intensity interval training

Full size table

Muscle carnitine content was not affected following 12 weeks of LC supplementation alone [11, 12]. On the other hand, LC supplementation in combination with CHO effectively elevated muscle TC after 12 [6] and 24 weeks [5]. Moreover, 12 weeks of supplementation alone [13], or in combination with CHO [6] promote the expression‎ of the genes related to fatty acids and carnitine metabolism.

Twenty-four-weeks of LC supplementation alone did not affect muscle strength in healthy aged women [15], but significantly increased muscle mass, improved physical effort tolerance and cognitive function in centenarians [14].

In two studied groups of healthy aged woman, LC supplementation alone [16, 17], or in combination with L-leucine [18], induced an increase of fasting plasma TMAO levels. However, higher TMAO was not associated with determined inflammatory [16] nor oxidative stress [17] markers. Moreover, despite elevated TMAO, LC supplementation together with resistance training induced positive changes in mitochondrial DNA methylation of platelets [18].

근육 카르니틴 함량은

12주간 LC 단독 보충 후에는 영향을 받지 않았습니다 [11, 12].

반면, 탄수화물(CHO)과 병용한 LC 보충제는

12주 [6] 및 24주 [5] 후에 근육 총 카르니틴(TC)을 효과적으로 증가시켰습니다.

더욱이, 12주간의 단독 보충 [13] 또는 CHO와의 병용 [6]은 지방산 및 카르니틴 대사와 관련된 유전자 발현을 촉진했습니다.

건강한 노년 여성에게 24주간 LC 단독 보충은

근력에 영향을 미치지 않았지만 [15],

100세인(centenarians)의 근육량을 유의미하게 증가시키고

신체 활동 내성 및 인지 기능을 개선했습니다 [14].

건강한 노년 여성의 두 연구군에서

LC 단독 보충 [16, 17] 또는

L-류신 [18]과의 병용은 공복 혈장 TMAO 수치를 증가시켰습니다.

그러나

더 높은 TMAO 수치는

특정 염증 [16] 또는 산화 스트레스 [17] 표지자와 관련이 없었습니다.

더욱이, TMAO가 증가했음에도 불구하고,

저항 훈련과 함께 LC 보충은

혈소판의 미토콘드리아 DNA 메틸화에 긍정적인 변화를 유도했습니다 [18].

Discussion

The present findings have been debated in the six separate paragraphs, and for a better picture of LC supplementation, other studies were also disputed.

“Fat burner”

It has been assumed that LC supplementation, by increasing muscle carnitine content, optimizes fat oxidation and consequently reduces its availability for storage [19]. Nevertheless, the belief that carnitine is a slimming agent has been negated in the middle of 90s [20]. Direct measurements of carnitine in skeletal muscles failed to show any elevation in the muscle carnitine concentration following 14 days of 4 g/day [21], or 6 g/day [22] LC ingestion. These findings implied that LC supplementation was not able to increase fat oxidation and improve exercise performance by the proposed mechanism. Indeed, many original investigations, summarized in later review [4], indicated that LC supplementation lasting up to 4 weeks, neither increase fat oxidation nor improve performance during prolonged exercises.

Since LC concentration in skeletal muscles is higher than that of blood plasma, active uptake of carnitine must take place [23]. Stephens et al. [24] noted that 5 h steady-state hypercarnitinemia (~ 10-fold elevation of plasma carnitine) induced by the intravenous LC infusion does not affect skeletal muscle TC content. On the other hand, similar intervention in combination with controlled hyperinsulinemia (~ 150mIU/L) elevates TC in skeletal muscle by ~ 15% [24, 25]. Moreover, higher serum insulin maintained by the consumption of simple sugars resulted in augmented LC retention in healthy human subjects supplemented by LC for 2 weeks [26]. Based on these results, Authors suggested that oral ingestion of LC, combined with CHO for activation carnitine transport into the muscles, should take ~ 100 days to increase muscle carnitine content by ~ 10% [26]. This assumption has been confirmed in later studies [5,6,7]. These carefully conducted studies clearly showed that prolonged procedure (for ≥12 weeks) of a daily LC and CHO ingestion induced a raise of skeletal muscle TC levels [5,6,7], affecting exercise metabolism [5], improving performance [5] and energy expenditure [6], without altering body composition [6]. The lack of body fat stores loss may be explained by the 18% increase in body fat mass associated with CHO supplementation alone, noted in the control group [6].

Nevertheless, 12 weeks of LC supplementation 2 g/day applied without CHO, elevated muscle TC only in vegetarian but not in omnivores [12]. Neither exercise metabolism nor muscle metabolites were modified by augmented TC in vegetarian [12].

현재까지의 연구 결과는 6개의 개별 단락에서 논의되어 왔으며, LC 보충제에 대한 더 나은 이해를 위해 다른 연구들도 함께 검토되었습니다.

"지방 연소제"

LC 보충제가

근육 카르니틴 함량을 증가시켜 지방 산화를 최적화하고

결과적으로 지방 저장 가능성을 줄이는 것으로 가정되어 왔습니다 [19].

그러나

카르니틴이 체중 감량제라는 믿음은

1990년대 중반에 부정되었습니다 [20].

14일 동안 4g/일 [21] 또는 6g/일 [22]의 LC 섭취 후

골격근의 카르니틴 농도 상승을 직접 측정한 결과는 보여주지 못했습니다.

이러한 발견은

LC 보충제가 제안된 메커니즘을 통해 지방 산화를 증가시키거나

장기적인 운동 성능을 향상시키지 못한다는 것을 암시했습니다.

실제로, 이후 리뷰 [4]에 요약된 많은 원본 연구들은

4주까지 지속된 LC 보충이 장기적인 운동 중 지방 산화를 증가시키거나 성능을 향상시키지 못했다고 지적했습니다.

골격근의 LC 농도가 혈장보다 높기 때문에

카르니틴의 능동적인 흡수가 반드시 일어나야 합니다 [23].

Stephens 등 [24]은

정맥 LC 주입으로 유도된 5시간의 안정 상태 과카르니틴혈증(혈장 카르니틴 약 10배 증가)이

골격근 TC(총 카르니틴) 함량에 영향을 미치지 않는다고 언급했습니다.

반면,

통제된 과인슐린혈증(약 150mIU/L)과 결합된 유사한 개입은

골격근의 TC를 약 15% 증가시킵니다 [24, 25].

또한,

단순당 섭취를 통해 유지된 높은 혈청 인슐린은

2주 동안 LC를 보충한 건강한 인간 피험자에서 LC 보유량을 증가시켰습니다 [26].

이러한 결과를 바탕으로 저자들은

LC의 경구 섭취를 근육 내 카르니틴 수송 활성화를 위한 CHO(탄수화물)와 결합하면

근육 카르니틴 함량을 약 10% 증가시키는 데

약 100일이 걸릴 것이라고 제안했습니다 [26].

이 가정은 이후 연구들 [5, 6, 7]에서 확인되었습니다.

이 신중하게 수행된 연구들은 매일 LC와 CHO를 섭취하는 장기적인 절차(≥12주 동안)가 골격근 TC 수치를 증가시키고 [5, 6, 7], 신체 구성에 변화를 주지 않으면서 [6] 운동 대사에 영향을 미치고 [5], 성능을 개선하며 [5], 에너지 소비를 증가시킨다는 것을 명확하게 보여주었습니다 [6].

체지방 저장 손실이 없었던 것은 대조군에서 CHO 보충제 단독과 관련된 체지방량 18% 증가로 설명될 수 있습니다 [6].

그럼에도 불구하고,

CHO 없이 적용된 12주간의 2g/일 LC 보충은 채식주의자에서만 근육 TC를 증가시켰고

잡식성 동물에서는 그렇지 않았습니다 [12].

채식주의자에서 증가된 TC에 의해 운동 대사나 근육 대사 산물은 변하지 않았습니다 [12].

Skeletal muscle protein balance regulation

Skeletal muscle mass depends on the rates of protein synthesis and degradation. Elevated protein synthesis and attenuated proteolysis are observed during muscle hypertrophy. Both of these processes are mainly regulated by the signaling pathway: insulin-like growth factor-1 (IGF-1) – phosphoinositide-3-kinase (PI3K) – protein kinase B (Akt) – mammalian target of rapamycin (mTOR). The activation of mTOR leads to phosphorylation and activation of S6 kinases (S6Ks) and hyperphosphorylation of 4E-binding proteins (4E-BPs), resulting in the acceleration of protein synthesis. At the same time, Akt phosphorylates and inactivates forkhead box O (FoxO), thereby inhibit the responsible for proteolysis ubiquitin ligases: muscle-specific RING finger-1 (MuRF-1) and muscle atrophy F-box protein (atrogin-1), (for review see [27,28,29]).

The association between LC supplementation and the regulation of metabolic pathways involved in muscle protein balance have been shown in several animal studies (Fig. 2) [30,31,32,33,34,35]. Four weeks of LC supplementation in rats increased plasma IGF-1 concentration [33]. Elevated circulating IGF-1 led to an activation of the IGF-1–PI3K–Akt signalling pathway, causing augmented mTOR phosphorylation and higher phospho-FoxO/total FoxO ratio in skeletal muscle of LC supplemented rats [33]. FoxO inactivation attenuated MURF-1 expression‎ in quadriceps femoris muscle of supplemented rats (compared to control) [33]. Moreover, LC administrated for 2 weeks suppresses atrogin-1 messenger RNA (mRNA) level in suspended rats’ hindlimb [35], and only 7 days of LC administration downregulates MuRF-1 and atrogin-1 mRNAs reducing muscle wasting in a rat model of cancer cachexia [32]. All these findings together might suggest that LC supplementation protect muscle from atrophy, especially in pathophysiological conditions.

골격근 단백질 균형 조절

골격근량은

단백질 합성 및 분해 속도에 따라 달라집니다.

근육 비대 시에는

단백질 합성 증가와 단백질 분해 감소가 관찰됩니다.

이 두 과정은

주로 인슐린 유사 성장 인자-1(IGF-1) – 포스포이노시티드-3-키나아제(PI3K) – 단백질 키나아제 B(Akt) – 랩토마이신 표적 단백질(mTOR) 신호 전달 경로에 의해 조절됩니다.

mTOR의 활성화는

S6 키나아제(S6Ks)의 인산화 및 활성화와 4E-결합 단백질(4E-BPs)의 과인산화를 유도하여

단백질 합성을 가속화합니다.

동시에

Akt는 FoxO(forkhead box O)를 인산화하고 비활성화하여

단백질 분해를 담당하는 유비퀴틴 리가아제인

근육 특이적 RING-finger-1(MuRF-1) 및 근육 위축 F-box 단백질(atrogin-1)을 억제합니다

(리뷰 [27, 28, 29] 참조).

LC 보충제와 근육 단백질 균형에 관여하는 대사 경로 조절 간의 연관성은

여러 동물 연구에서 나타났습니다 (그림 2) [30, 31, 32, 33, 34, 35].

쥐에게 4주간 LC 보충제를 투여한 결과 혈장 IGF-1 농도가 증가했습니다 [33].

증가된 순환 IGF-1은

IGF-1–PI3K–Akt 신호 전달 경로를 활성화시켜

LC 보충 쥐의 골격근에서 mTOR 인산화 증가 및 인산화 FoxO/총 FoxO 비율 증가를 유발했습니다 [33].

FoxO 비활성화는

보충 쥐의 대퇴사두근에서 MURF-1 발현을 감소시켰습니다 (대조군과 비교 시) [33].

더욱이,

2주 동안 투여된 LC는

현수 쥐의 뒷다리에서 atrogin-1 mRNA 수치를 억제하며 [35],

단 7일의 LC 투여만으로도 암 악액질 쥐 모델에서 MuRF-1 및 atrogin-1 mRNA를 하향 조절하여 근육 소모를 줄였습니다 [32].

이 모든 발견들은

LC 보충제가 특히 병태생리학적 조건에서 근육 위축을 보호할 수 있음을 시사합니다.

Fig. 2

The association between LC supplementation and the regulation of metabolic pathways involved in muscle protein balance. L-carnitine (LC); insulin-like growth factor-1 (IGF-1); phosphoinositide-3-kinase (PI3K); protein kinase B (Akt); mammalian target of rapamycin (mTOR); forkhead box O (FoxO); muscle-specific RING finger-1 (MuRF-1); muscle atrophy F-box (atrogin-1);

In fact, administration of acetyl-L-carnitine 3 g/day for 5 months in HIV-seropositive patients induced ten-fold increase in serum IGF-1 concentration [36]. Conversely, neither 3 weeks LC supplementation in healthy, recreationally weight-trained men [37], nor 24 weeks LC supplementation in aged women [15] did not affect circulating IGF-1 level concentration. Various effects might be due to different IGF-1 levels; significantly lower in the HIV-seropositive patients than in healthy subjects [38]. Additionally, 8 weeks of LC supplementation in healthy older subjects, did not change total and phosphorylated mTOR, S6K and 4E-BP proteins level of vastus lateralis muscle [39]. It must be highlighted that rat skeletal muscle TC increases ~ 50–70% following 4 weeks of LC supplementation [33, 34], whereas comparable elevation has never been observed in human studies, even after 24 weeks of supplementation [5, 7].

Body composition

These findings altogether suggest that prolonged LC supplementation might affect body composition in specific conditions.

Obesity

A recent meta-analysis, summarized studies focused on LC supplementation for a prolonged time (median 3 months) [40]. Pooled results demonstrated a significant reduction in weight following LC supplementation, but the subgroups analysis revealed no significant effect of LC on body weight in subjects with body mass index (BMI) below 25 kg/m2. Therefore, authors suggested that LC supplementation may be effective in obese and overweight subjects. Surprisingly, intervention longer than 24 weeks showed no significant effect on BMI [40].

신체 구성 이러한 발견들은 종합적으로 장기적인 LC 보충이 특정 조건에서 신체 구성에 영향을 미칠 수 있음을 시사합니다.

비만 최근의 메타분석은 장기간(중앙값 3개월) LC 보충에 초점을 맞춘 연구들을 요약했습니다 [40]. 종합된 결과는 LC 보충 후 체중의 유의미한 감소를 보여주었지만, 하위 그룹 분석에서는 체질량 지수(BMI) 25 kg/m2 미만인 피험자에서 LC가 체중에 유의미한 영향을 미치지 않는 것으로 나타났습니다. 따라서 저자들은 LC 보충이 비만 및 과체중 피험자에게 효과적일 수 있다고 제안했습니다. 놀랍게도, 24주를 초과하는 개입은 BMI에 유의미한 영향을 미치지 않았습니다 [40].

Training

It has been assumed that a combination of LC supplementation with increased energy expenditure may positively affect body composition. However, either with aerobic [41, 42] or resistance [43] training, LC supplementation has not achieved successful endpoint. Six weeks of endurance training (five times per week, 40 min on a bicycle ergometer at 60% maximal oxygen uptake) together with LC supplementation (4 g/day) does not induce a positive effect on fat metabolism in healthy male subjects (% body fat 17.9 ± 2.3 at the beginning of the study) [41]. Similarly, lack of LC effect has been reported in obese women [42]. Eight weeks of supplementation (2 g/day) combined with aerobic training (3 sessions a week) had no significant effects on body weight, BMI and daily dietary intake in obese women [42].

In the recent study, LC supplementation 2 g/day has been applied in combination with a resistance training program (4 days/week) to healthy men (age range 18–40 y.o.), for 9 weeks [43]. Body composition, determined by dual energy X-ray absorptiometry, indicated no significant effect in fat mass and fat-free mass due to supplementation. Moreover, LC administration did not influence bench press results. The number of leg press repetitions and the leg press third set lifting volume increased in the LC group compared to the placebo group [43]. Different LC effect in the limbs may be associated with the higher rates of glycogenolysis during arm exercise at the same relative intensity as leg exercise [44].

훈련

LC 보충과 에너지 소비 증가의 조합이 신체 구성에 긍정적인 영향을 미칠 수 있다고 가정되어 왔습니다. 그러나 유산소 [41, 42] 또는 저항 [43] 훈련과 병용했을 때, LC 보충은 성공적인 결과를 달성하지 못했습니다. 6주간의 지구력 훈련(주 5회, 자전거 에르고미터에서 최대 산소 섭취량의 60%로 40분)과 LC 보충(4g/일)을 함께 실시해도 건강한 남성 피험자(연구 시작 시 체지방률 17.9 ± 2.3%)의 지방 대사에 긍정적인 영향을 미치지 않았습니다 [41]. 유사하게, 비만 여성에게서 LC 효과의 부족이 보고되었습니다 [42]. 8주간의 보충(2g/일)과 유산소 훈련(주 3회)을 병용한 결과, 비만 여성의 체중, BMI 및 일일 식이 섭취량에 유의미한 영향을 미치지 않았습니다 [42]. 최근 연구에서는 건강한 남성(18-40세)에게 9주 동안 저항 훈련 프로그램(주 4일)과 함께 LC 보충제 2g/일을 적용했습니다 [43]. 이중 에너지 X선 흡수계(DXA)로 측정한 신체 구성은 보충으로 인한 지방량 및 무지방량에 유의미한 영향이 없음을 나타냈습니다. 또한, LC 투여는 벤치프레스 결과에 영향을 미치지 않았습니다. LC 그룹에서 위약 그룹에 비해 레그 프레스 반복 횟수와 레그 프레스 3세트 리프팅 볼륨이 증가했습니다 [43]. 사지에서의 LC 효과 차이는 다리 운동과 동일한 상대 강도의 팔 운동 시 글리코겐 분해율이 더 높다는 점과 관련이 있을 수 있습니다 [44].

Sarcopenia

Aged people have accelerated protein catabolism, which is associated with muscle wasting [45]. LC could increase the amount of protein retention by inhibition of the proteolytic pathway. Six months of LC supplementation augmented fat free mass and reduced total body fat mass in centenarians [14]. Such effect was not observed in elder women (age range 65–70 y.o.) after a similar period of supplementation [15]. The effectiveness of LC supplementation may result from the age-wise distribution of sarcopenia. The preval‎ence of sarcopenia increased steeply with age, reaching 31.6% in women and 17.4% in men older than 80 years [46]. In subjects below 70 years presarcopenia, but not sarcopenia symptoms were noted [46].

근감소증 

노년층은 단백질 이화작용이 가속화되어 근육 소모와 관련이 있습니다 [45]. LC는 단백질 분해 경로를 억제하여 단백질 보유량을 증가시킬 수 있습니다. 6개월간의 LC 보충은 100세인(centenarians)의 무지방량을 증가시키고 총 체지방량을 감소시켰습니다 [14]. 그러나 유사한 보충 기간 후 고령 여성(65-70세)에게서는 이러한 효과가 관찰되지 않았습니다 [15]. LC 보충의 효과는 근감소증의 연령별 분포에 기인할 수 있습니다. 근감소증의 유병률은 연령에 따라 급격히 증가하여 80세 이상 여성의 31.6%, 남성의 17.4%에 달했습니다 [46]. 70세 미만 피험자에게서는 근감소증 증상이 아닌 전근감소증(presarcopenia)이 나타났습니다 [46].

Oxidative imbalance and muscle soreness

Muscle damage may occur during exercise, especially eccentric exercise. In the clearance of damaged tissues assist free radicals produced by neutrophils. Therefore, among other responses to exercise, neutrophils are released into the circulation. While neutrophil-derived reactive oxygen species (ROS) play an important role in breaking down damaged fragments of the muscle tissue, ROS produced in excess may also contribute to oxidative stress (for review see [47, 48].

Based on the assumption that LC may provide cell membranes protection against oxidative stress [49], it has been hypothesized that LC supplementation would mitigate exercise-induced muscle damage and improve post-exercise recovery. Since plasma LC elevates following 2 weeks of supplementation [21, 22], short protocols of supplementation may be considered as effective in attenuating post-exercise muscle soreness. The findings indicated that 3 weeks of LC supplementation, in the amount 2-3 g/day, effectively alleviated pain [50,51,52,53]. It has been shown, through magnetic resonance imaging technique that muscle disruption after strenuous exercise was reduced by LC supplementation [37, 51]. This effect was accompanied by a significant reduction in released cytosolic proteins such as myoglobin and creatine kinase [50, 52, 53] as well as attenuation in plasma marker of oxidative stress - malondialdehyde [51, 53, 54]. Furthermore, 9 weeks of LC supplementation in conjunction with resistance training revealed a significant increase of circulating total antioxidant capacity and glutathione peroxidase activity and decrease in malondialdehyde concentration [43].

산화 불균형 및 근육통

운동 중, 특히 편심성 운동 중에 근육 손상이 발생할 수 있습니다. 손상된 조직 제거에는 호중구(neutrophils)가 생성하는 자유 라디칼이 도움이 됩니다. 따라서 운동에 대한 다른 반응 중에서도 호중구가 혈액으로 방출됩니다. 호중구 유래 반응성 산소종(ROS)은 손상된 근육 조직 조각을 분해하는 데 중요한 역할을 하지만, 과도하게 생성된 ROS는 산화 스트레스에도 기여할 수 있습니다 (리뷰 [47, 48] 참조). LC가 세포막을 산화 스트레스로부터 보호할 수 있다는 가정에 따라 [49], LC 보충이 운동 유발 근육 손상을 완화하고 운동 후 회복을 개선할 것이라는 가설이 세워졌습니다. 2주 보충 후 혈장 LC가 증가하므로 [21, 22], 단기 보충 프로토콜은 운동 후 근육통 완화에 효과적일 수 있습니다. 연구 결과에 따르면 3주간 2-3g/일의 LC 보충은 통증을 효과적으로 완화했습니다 [50, 51, 52, 53]. 자기공명영상(MRI) 기술을 통해 격렬한 운동 후 근육 손상이 LC 보충으로 감소하는 것으로 나타났습니다 [37, 51]. 이러한 효과는 미오글로빈 및 크레아틴 키나아제와 같은 방출된 세포질 단백질의 유의미한 감소 [50, 52, 53]뿐만 아니라 산화 스트레스의 혈장 표지자인 말론디알데하이드의 완화 [51, 53, 54]와 함께 나타났습니다. 또한, 저항 훈련과 병행한 9주간의 LC 보충은 순환하는 총 항산화 능력 및 글루타티온 퍼옥시다아제 활성의 유의미한 증가와 말론디알데하이드 농도의 감소를 보였습니다 [43].

Risks of TMAO

In 1984 Rebouche et al. [55], showed that rats, orally receiving radiolabeled LC, metabolized it to γ-butyrobetaine (up to 31% of the administered dose, present primary in feces) and TMAO (up to 23% of the administered dose, present primary in urine). On the contrary, these metabolites were not produced by the rats receiving the isotope intravenously and germ-free rats receiving the tracer orally, suggesting that orally ingested LC is in part degraded by the gut’s microorganisms [55]. Similar observations were noted in later human studies [56, 57], with the peak serum TMAO observed within hours following oral administration of the tracer [56]. Prolonged LC treatment elevates fasting plasma TMAO [16,17,18, 58, 59]. Three months of oral LC supplementation in healthy aged women induced ten-fold increase of fasting plasma TMAO, and this level remained elevated for the further 3 months of supplementation [16]. Four months after cessation of LC supplementation, plasma TMAO reached a pre-supplementation concentration, which was stable for the following 8 months [60].

In 2011 Wang et al. [61] suggested TMAO as a pro-atherogenic factor. Since diets high in red meat have been strongly related to heart disease and mortality [62], LC has been proposed as the red meat nutrient responsible for atherosclerosis promotion [8]. As a potential link between red meat consumption and the increasing risk of cardiovascular disease, TMAO has been indicated [8]. Numerous later studies have shown the association between increased plasma TMAO levels with a higher risk of cardiovascular events [63,64,65,66]. The recent meta-analyses indicated that in patients with high TMAO plasma level, the incidence of major adverse cardiovascular events was significantly higher compared with patients with low TMAO levels [67], and that all-cause mortality increased by 7.6% per each 10 μmol/L increment of TMAO [68].

Since red meat is particularly rich in LC [69], dietary intervention in healthy adults, indicated a significant increase in plasma and urine TMAO levels following 4 weeks of the red meat-enriched diet [70]. The rise of plasma TMAO was on average three-fold compared with white meat and non-meat diets [70]. Conversely, habitual consumption of red, processed or white meat did not affect plasma TMAO in German adult population [71]. Similarly, a minor increase in plasma TMAO was observed following red meat and processed meat consumption in European multi-center study [72].

In the previous century, the underlined function of TMAO was the stabilization of proteins against various environmental stress factors, including high hydrostatic pressure [73]. TMAO was shown as widely distributed in sea animals [74], with concentration in the tissue increasing proportionally to the depth of the fishes natural environment [75]. Consequently, fish and seafood nutritional intake has a great impact on TMAO level in the human body [76], significantly elevating also plasma TMAO concentration [72]. Therefore, link between plasma TMAO and the risk of cardiovascular disease [8] seems like a paradox, since more fish in the diet reduces this risk [77].

Not only dietary modification may affect TMAO plasma levels. Due to TMAO excretion in urine [56, 57], in chronic renal disease patients, TMAO elimination from the body fails, causing elevation of its plasma concentration [78]. Therefore, higher plasma TMAO in humans was suggested as a marker of kidney damage [79]. It is worthy to note that cardiovascular disease and kidney disease are closely interrelated [80] and diminished renal function is strongly associated with morbidity and mortality in heart failure patients [81]. Moreover, decreased TMAO urine excretion is associated with high salt dietary intake, increasing plasma TMAO concentration [82].

The relation between TMAO and chronic disease can be ambiguous, involving kidney function [79], disturbed gut-blood barrier [83], or flavin-containing monooxygenase 3 genotype [84]. Thus, whether TMAO is an atherogenic factor responsible for the development and progression of cardiovascular disease, or simply a marker of an underlined pathology, remains unclear [85].

Adverse effects

Carnitine preparations administered orally can occasionally cause heart-burn or dyspepsia [86]. No adverse events associated with LC administration were recorded at a dose 6 g/day for 12 months of supplementation in the patients with acute anterior myocardial infarction [87], or at a dose 1.274 g/day (range 0.3–3 g/day) and duration 348 days (range 93–744 days) in patients with liver cirrhosis [88]. Summarizing the risk associated with LC supplementation Hathcock and Shao [89] indicated that intakes up to 2 g/day are safe for chronic supplementation.

Although the optimal dose of LC supplementation for myocardial infarction is 3 g/day in terms of all-cause mortality [90], even lower LC intake elevates fasting plasma TMAO [16,17,18, 58, 59], which is ten-fold higher than control after 3 months of supplementation [16, 17]. It is worthy to mention that Bakalov et al. [91] analyzing European Medicine Agency database of suspected adverse drug reaction, noticed 143 cases regarding LC.

Strengths and limitations

The strength of this review is a focus on the period of LC treatment, very important aspect often missed in many articles dealing with this supplement. To date, only few studies have examined the effects of LC supplementation for at least 12 weeks, which is, on the other hand, the main limitation of the current review. This limitation is also magnified by the varied design of the studies available including different supplementation protocols and outcome measures. There is also a high degree of heterogeneity among participants of the analyzed studies. Therefore, the results should be taken with caution, and more research is required before definitive recommendations.

Conclusions

Lasting for several years opinion that LC supplementation does not change metabolism, especially exercise metabolism, is based mostly on short-term supplementation protocols. Nevertheless, LC is still used by elite [9] and sub-elite [10] athletes. Recent studies suggest that LC supplementation may elevate muscle TC content; therefore, modify muscle fuel metabolism and performance during the exercise. Due to insulin-mediated LC transport to the muscle, oral administration regimen should be combined with CHO. Because of LC poor bioavailability, it is likely that the supplementation protocol would take at least 3 months. Shorter period of supplementation may be effective in prevention of exercise-induced muscle damage, but not metabolic changes.

On the other hand, it is also clear that prolonged LC supplementation elevates fasting plasma TMAO [16,17,18, 58, 59], compound supposed to be pro-atherogenic [61]. Therefore, additional studies focusing on long-term supplementation and its longitudinal effect on the TMAO metabolism and cardiovascular system are needed.

Availability of data and materials

Not applicable.

Abbreviations

LC:

L-carnitine

TC:

Total carnitine

TMAO:

Trimethylamine-N-oxide

CHO:

Carbohydrates

IGF-1:

Insulin-like growth factor-1

PI3K:

Phosphoinositide-3-kinase

Akt:

Protein kinase B

mTOR:

Mammalian target of rapamycin

S6K:

S6 kinase

4E-BP:

4E-binding protein

FoxO:

Forkhead box O

MuRF-1:

Muscle-specific RING finger-1

atrogin-1:

Muscle atrophy F-box

mRNA:

Messenger RNA

BMI:

Body mass index

ROS:

Reactive oxygen species

References

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