Re: TrP 통증유발점 발생의 원인... 최신 논문 이해!!

[문형철]

https://pmc.ncbi.nlm.nih.gov/articles/PMC10179372/

A New Unified Theory of Trigger Point Formation: Failure of Pre- and Post-Synaptic Feedback Control Mechanisms - PMC

근막통증증후군(Myofascial Pain Syndrome, MPS)의 핵심 병변인

근막통증 유발점(Myofascial Trigger Point, TrP)의 형성 기전에 대한

새로운 통합 가설(new unified hypothesis)을 제시하는 개념적 리뷰(conceptual review)입니다.

Simons의 2004년 Integrated Hypothesis(에너지 위기 모델)를 넘어,

보호 피드백 기전의 실패와 이온 채널병(ion channelopathies)을 중심으로

TrP 형성을 설명합니다.

1. 배경: 기존 가설의 한계와 새로운 관점

전통적인 Simons의 Integrated Hypothesis는

운동종판(motor endplate) 기능 이상

→ 지속적 acetylcholine (ACh) 방출

→ 국소 근육 contracture

→ 허혈(ischemia)

→ 에너지 위기(ATP 저하)

→ TrP 형성으로 설명합니다.

그러나

TrP가 왜 특정 상황에서만 형성되는지,

즉 “기원(origin)”에 대한 ‘black box’가 남아 있었습니다.

Gerwin의 새로운 가설 핵심:

• 근육 과활동(intense or repetitive overload), 저 ATP, 저 pH 같은 스트레스 상황에서 근육 보호 피드백 기전(pre- and post-synaptic feedback control mechanisms)이 실패하면,
• 세포 내 Ca²⁺ 과다 축적 → 지속적 actin-myosin cross-bridging(교차 결합) → contraction knot(수축 결절) 형성 → nociceptive system 활성화 → TrP 발생.

이 가설은 일부 TrP(subset of TrPs)에 적용되며, 다인자적(multifactorial) 원인을 인정합니다.

leagravetherapy.co.uk

aneskey.com

(위 그림: 신경근접합(neuromuscular junction, NMJ) 구조와 ACh 방출 과정. 정상 상황에서 Ca²⁺ 유입 → ACh vesicle 방출 → postsynaptic receptor 결합 → 근육 수축.)

https://www.pnas.org/doi/10.1073/pnas.1524272113

이 논문은
2016년 PNAS에 발표된 "Sympathetic innervation controls homeostasis of neuromuscular junctions in health and disease"입니다. (저자: Muzamil Majid Khan et al.)

논문의 핵심 내용 (간단 요약)

• 교감신경(sympathetic neurons)이 골격근의 신경근 접합부(neuromuscular junctions, NMJ)에 직접적으로 밀접하게 분포하며, 대부분의 NMJ(약 90-95%)를 innervate한다는 사실을 처음으로 보여줌.
• 교감신경 자극이 NMJ postsynaptic β2-아드레날린 수용체(ADRB2)를 활성화 → cAMP 증가 → PPARGC1A(전사 조절 인자)의 핵 내 이동을 유도.
• 이 과정이 NMJ 유지·기능에 필수적이며, sympathectomy(교감신경 제거) 시 NMJ 크기 감소, 기능 저하가 발생하지만 clenbuterol 같은 sympathomimetic(교감신경 모방 약물)로 회복 가능.
• 특히 myasthenic mice(중증 근무력증 모델)에서 NMJ 이상을 정상화하는 효과를 보임.
• 결론: 교감신경 입력이 NMJ homeostasis(항상성 유지)에 중요하며, 자율신경 장애나 근육 약화 질환에서 치료적 잠재력이 있음.

이 논문을
지지·확인·확장하는 최신 논문들 (2021~2024년 중심)

원 논문 이후 여러 연구에서
교감신경-NMJ 관계, β2-아드레날린 수용체 역할, sympathomimetic의 NMJ 보호 효과 등이
재확인되고 확장되었습니다.

주요 예시:

2024년: "Sympathetic innervation in skeletal muscle and its role at the neuromuscular junction" (Rudolf et al.) — 원 논문을 직접 인용하며, 교감신경이 skeletal muscle과 NMJ에서 하는 역할을 종합적으로 검토. NMJ 유지에 대한 sympathetic input의 중요성을 재강조.

신경근 접합부(NMJ)는
운동신경과 골격근 섬유 사이의 시냅스로,
자발적 근육 운동을 담당합니다.

전통적으로 NMJ는
운동신경-근육-말초 Schwann 세포로 이루어진 tripartite 시냅스로 여겨졌습니다.

교감신경의 NMJ 분포에 대한 증거는
약 100년 전부터 있었지만,
NMJ의 유지(maintenance)와 조절(modulation)에서 교감신경의 필수적 역할은
최근에야 명확히 밝혀졌습니다.

이 발견은
다양한 임상 질환의 병태생리를 이해하고,
골격근 장애에 대한 수술 및 치료 전략을 최적화하는 데 도움을 줄 수 있습니다.

1. 상단 전체 구조 (교감신경 경로)
   • Spinal cord(척수)에서 시작된 교감신경이 Sympathetic trunk(교감신경 줄기)를 통해 내려옴.
   • Sympathetic axon(교감신경 축색돌기)이 혈관(Blood vessel)을 따라 근육으로 들어가 NMJ 부위까지 도달.
   • 운동신경(Motorneuron) 끝부분에서 synaptic vesicle(SV, 시냅스 소포)이 acetylcholine을 방출하여 nAChR(니코틴 아세틸콜린 수용체, 청록색 구조)를 활성화.
2. 교감신경 신호 전달 (Muscle cell 내부)
   • Sympathetic axon에서 NE (norepinephrine)가 방출됨 (녹색 원).
   • NE가 β2-아드레날린 수용체 등에 결합 → Gs 단백질 활성화 → cAMP 증가 → PKA 활성화.
   • 이로 인해 HDAC4 / myogenin 경로가 억제됨 (점선 화살표).
   • Gi2 단백질도 관여 (복잡한 조절).
3. NMJ postsynaptic 부위의 주요 효과 (오른쪽 박스)
   • 단백질 분해 억제:
     • Atrogenes ↓ (특히 MuRF-1 ↓) → ubiquitin- proteasome 시스템 억제.
     • Calpastatin ↑ (calpain 억제제) → calpain (칼슘 의존성 protease) ↓.
   • 결과: nAChR의 분해(Degradation)가 줄어들고, 표면 nAChR 안정성 ↑.
   • PGC-1α ↑ (미토콘드리아 생합성·근육 대사 관련 전사 조절 인자).
4. 추가 영향
   • 운동신경 쪽: synaptic vesicle release 동기화(synchrony)와 quantal content 증가.
   • 전체적으로 교감신경은 NMJ의 구조적·기능적 항상성(homeostasis) 유지에 필수적.

한 줄 핵심 의미
교감신경이 NMJ에 직접 co-innervate(공동 신경지배)하면서 노르에피네프린 → cAMP/PKA → 분해 억제 + PGC-1α 활성화 경로를 통해 nAChR를 안정화시키고, 근육 기능을 유지한다는 모식도






주요 내용 요약
이 논문은 리뷰 형식으로, 교감신경이 골격근과 특히 NMJ에서 하는 역할을 종합적으로 정리합니다. 과거에는 교감신경이 주로 혈관 평활근(vasomotor control)을 조절한다고 생각되었으나, 최근 연구들은 교감신경이 NMJ에 직접 co-innervate(공동 신경지배)하며 기능적으로 중요하다는 점을 강조합니다.


1. 형태학적 증거 (Morphological evidence)

• 과거(19~20세기 초) 금/은 염색 연구에서 NMJ 근처에 교감신경 섬유가 관찰되었으나, 오랫동안 무시됨.
• 2016년 Khan et al. (PNAS) 연구를 핵심적으로 인용: 광학 조직 투명화(optical tissue clearing) + 3D confocal microscopy를 통해 마우스 횡격막, EDL, tibialis anterior 등에서 교감신경(TH 양성) 축색돌기가 NMJ 바로 옆에 존재함을 명확히 증명.
• 출생 시 NMJ의 약 40%에 TH-positive plaque가 관찰되며, 성체에서는 80% 이상으로 증가 → 교감신경 co-innervation이 규칙적 현상임.

2. 기능적 역할 (Functional role)

• Gain-of-function (자극 시): 교감신경 활성화 또는 β2-아드레날린 수용체(ADRB2) 작용제 → cAMP 증가 → PGC-1α 핵 이동, miniature endplate potential 빈도 및 quantal content 증가. (시냅스 전달 강화)
• Loss-of-function (제거 시): sympathectomy (화학적/외과적 교감신경 제거) → 근육량 감소, NMJ 크기 축소, nAChR 안정성 저하, 근력 저하.
  • 이러한 변화는 clenbuterol 같은 sympathomimetic 약물로 회복 가능 (Khan et al. 2016 직접 인용).
• 메커니즘: cAMP/PKA 경로를 통해 HDAC4/myogenin 축 억제 → atrogene(MuRF1 등)과 calpain 활성 저하 → nAChR 분해 억제 → NMJ 안정성 유지.

3. 임상적 함의

• 교감신경 기능 이상이 중증 근무력증(myasthenia gravis), ALS, sarcopenia(근감소증) 등의 병태에 기여할 가능성.
• sympathomimetics(β2 작용제 등)가 NMJ 보호 및 근육 영양(trophism) 유지에 치료 잠재력 있음.
• 단, α1/β1 수용체는 오히려 spontaneous release를 억제하는 등 다중 adrenoceptor 효과가 복잡함.

2024년: "β2-Adrenoceptors activation regulates muscle trophic-related gene expression‎" (Abdalla-Silva et al.) — β2-아드레날린 수용체 활성화가 근육 trophic(영양 공급) 관련 유전자 발현을 조절한다는 점을 확인. 원 논문의 ADRB2-cAMP-PPARGC1A 경로를 지지.

이 연구는
저항성 운동(Resistance Exercise, RE) 직후 β2-아드레날린 수용체(β2-AR)가 골격근에서
근육 성장(비대, hypertrophic) 관련 유전자와 근육 위축(atrophic) 관련 유전자를
어떻게 조절하는지 밝힌 실험 논문입니다.

주요 발견

• 한 번의 저항성 운동(RE, 사다리 오르기 모델) 후 혈중 노르에피네프린(NE)이 급격히 증가하고, 근육 내에서 CREB 인산화가 증가합니다.
• 이는 CREB 표적 유전자(Nr4a3, Sik1, Ppargc1a)의 발현을 증가시킵니다. 특히 Nr4a3는 급성 RE 반응의 핵심 조절자로 작용합니다.
• β2-AR 차단제를 투여하면:
  • hypertrophic 유전자(Nr4a3, Sik1) 발현이 유의하게 감소합니다.
  • atrophic(위축) 유전자(Mstn = myostatin, Murf1/Trim63, Atrogin-1/Mafbx) 발현이 과도하게 증가합니다.
• 즉, β2-AR 활성화는 운동 후 근육 성장 촉진 유전자를 자극하고, 위축 관련 유전자의 과도한 발현을 억제하는 보호 역할을 합니다.

결론
저항성 운동 중 교감신경계(Sympathetic Nervous System, SNS)에서 유리되는 카테콜아민이 β2-AR를 통해 작용하여, 근육의 적응(adaptation)에 중요한 역할을 한다는 분자적 증거를 제시합니다. 이는 이전 연구(Khan et al. 2016 등)에서 밝혀진 교감신경–NMJ–β2-AR 경로를 운동 맥락에서 뒷받침하는 결과


2023년: "Direct electrical stimulation impacts on neuromuscular junction and muscle" (Lee et al.) — NMJ와 근육에 대한 전기 자극 효과를 연구하며, sympathetic innervation의 역할을 참고로 인용.

이 연구는 장기적인 postsynaptic 신경근 차단(α-cobrotoxin 투여로 AChR 차단) 상태에서 직접 전기 자극(direct electrical stimulation)이 신경근 접합부(NMJ)의 형태학적 변화에 미치는 영향을 조사했습니다.
주요 발견

• Postsynaptic 차단만으로는 terminal Schwann cell (tSC)과 axonal sprouting(신경 및 교세포 돌기 성장)이 발생하지만, 탈신경(denervation)이나 presynaptic 차단보다는 정도가 약합니다.
• 한쪽 soleus 근육에만 만성 전기 자극(12시간/일, 5~8일)을 가하면:
  • 자극한 쪽뿐만 아니라 반대쪽(contralateral) 자극하지 않은 soleus에서도 tSC sprouting과 axonal sprouting이 유의하게 감소합니다 (8일 자극 시 tSC sprouts: 10.3 → 6.7~6.9 개/NMJ, p<0.001).
• RNA-seq 분석: 차단으로 인해 NMJ 관련 유전자 발현이 저하되었으나, 자극으로 양쪽 근육 모두에서 회복되는 효과를 보임.
• 자극한 쪽과 반대쪽 근육, 그리고 혈장에서 cytokine/chemokine(예: Ccl3, TGFβ1) 수준이 증가 → myokine을 통한 systemic crosstalk(근육 간/전신 교차 효과)를 시사.

결론
근육 활동(전기 자극)에 의해 유도된 활성 의존적 myokine이 NMJ sprouting을 억제하고, NMJ 형태와 유전자 발현을 보호하는 역할을 합니다. 이 효과는 자극한 근육뿐 아니라 반대쪽 근육에도 미치며, ICU-acquired weakness(중환자 근육 약화) 등에서 전기 자극 치료의 잠재적 기전을 제시합니다.
한 줄 요약: 직접 전기 자극은 postsynaptic 차단으로 인한 NMJ sprouting을 양쪽 다리 근육에서 모두 줄이고, myokine-mediated systemic 효과를 통해 NMJ 안정성을 유지


2023년: "Sympathetic modulation of hindlimb muscle contractility" (Hotta et al.) — 교감신경이 hindlimb muscle contractility(수축력)를 조절한다는 점을 보여주며, 원 논문의 NMJ homeostasis 기전을 뒷받침.

이 연구는 노화(aging) 과정에서 교감신경(sympathetic nerves)이 뒷다리 근육(triceps surae)의 수축력(contractility)에 미치는 영향을 비교한 실험 논문입니다. 특히 근육 수축 시 교감신경이 활성화되어 tetanic force(TF, 강직성 수축력)를 유지하는 피드백 메커니즘이 노화로 어떻게 변화하는지 조사했습니다.
주요 발견

• 교감신경 차단(LST transection) 시:
  • 젊은 쥐(4~9개월): TF가 12.9% 감소.
  • 노화 쥐(32~36개월): TF가 6.2%만 감소 (P=0.02, 젊은 쥐보다 유의하게 적음). → 노화 시 교감신경이 운동신경 유발 수축력을 지원하는 기여도가 절반 수준으로 감소.
• 교감신경 자극(LST stimulation, 5~20 Hz) 시:
  • 젊은 쥐: 5 Hz 이상에서 TF 증가 (3.8~5.8%).
  • 노화 쥐: 10 Hz 이상에서 TF 증가 (0.9~9.9%).
  • 전체 TF 증가 반응은 두 그룹 간 큰 차이 없음.
• 운동신경 자극과 무관한 muscle tonus(긴장도):
  • 교감신경 자극으로 인한 tonus 증가가 노화 쥐에서 유의하게 더 컸음 (P=0.03). 이는 주로 α-아드레날린 수용체를 통해 발생.
• α/β 차단제를 사용한 실험: TF 증강에는 α와 β 수용체 모두 관여, tonus 증가는 주로 α 수용체.

결론 및 함의
노화와 함께 운동 유발 근육 수축력을 교감신경이 지원하는 능력은 감소하지만, 운동과 무관한 근육 긴장도(tonus)는 오히려 증가합니다. 이 변화는 노인에서 나타나는 근력 저하(sarcopenia)와 운동 시 경직(rigidity) 현상을 설명할 수 있는 기전으로 제안됩니다.

한 줄 요약: 노화된 쥐에서는 교감신경이 근육 수축력을 유지해주는 피드백 효과가 약해지지만, 독립적인 근육 긴장도는 강해져 근력 저하와 운동 경직의 원인

2021~2022년: 여러 연구(예: Adrenoceptors Modulate Cholinergic Synaptic Transmission, Long-term Hand2 expression‎ 등)에서 β2-아드레날린 신호와 NMJ/근육 기능의 연관성을 추가로 확인.


이 논문은 아드레날린 수용체(adrenoceptors, α1/α2, β1/β2)가 신경근 접합부(NMJ)에서 콜린성(cholinergic) 시냅스 전달(즉, 운동신경에서 아세틸콜린(ACh) 방출 및 수용체 기능)을 어떻게 조절하는지 종합적으로 검토한 리뷰입니다.

주요 내용

• 교감신경 varicosities(말단)가 NMJ 바로 근처에 존재하며, 방출되는 노르에피네프린(NE) 등이 presynaptic(운동신경 말단)과 postsynaptic(근육 측) 아드레날린 수용체에 작용합니다.
• Presynaptic 효과:
  • α1 및 α2 수용체: spontaneous ACh 방출(miniature endplate potential, MEPP)과 evoked quantal release를 증가시키거나 감소시킬 수 있음 (조건에 따라 다름, 예: Ca²⁺ 농도 의존적).
  • β 수용체 (특히 β1): evoked ACh 방출의 동기화(synchronization)를 촉진 → Orbeli-Ginetsinsky 현상(교감신경 자극으로 근육 수축력 강화) 설명.
  • β2 수용체: quantal content(방출량) 증가, Ca²⁺ 채널 및 G-단백질(Gs/Gi) 경로 관여.
• Postsynaptic 효과:
  • β2-agonist (예: salbutamol, clenbuterol): nicotinic ACh receptor (nAChR) 클러스터링(cluster) 개선, 시냅스 면적 확대, 전달 효율 향상.
  • 특히 myasthenic (중증 근무력증) 모델에서 유익.
• Sympathectomy(교감신경 제거) 시 ACh 방출 감소, 수축력 저하가 발생.

Khan et al. (2016)와의 관계
Khan et al. (2016, PNAS)을 직접 인용하며, 교감신경이 NMJ homeostasis(항상성 유지)를 조절한다는 형태학적·기능적 증거를 배경으로 삼았습니다. 교감신경 co-innervation이 NMJ 유지에 필수적이며, 제거 시 위축과 AChR 감소가 일어난다는 점을 강조합니다.

결론 및 함의
NMJ에서 아드레날린 수용체는 presynaptic ACh 방출(량과 타이밍)과 postsynaptic 수용체 기능을 복잡하게 조절합니다. 효과는 수용체 subtype, 실험 조건(이온 농도), 근육 유형에 따라 다릅니다. β2-agonist가 시냅스 결함이 있는 질환(중증 근무력증, sarcopenia 등) 치료에 유망하다고 제안합니다.

한 줄 요약: 교감신경에서 유리되는 카테콜아민이 α/β 아드레날린 수용체를 통해 NMJ의 ACh 방출과 수용체 기능을 조절하며, 특히 β2 경로가 시냅스 전달 강화와 NMJ 유지에 중요하다는 리뷰

2. TrP의 객관적 특징 (Table 1 요약)

논문은 TrP의 전기생리학적·생화학적·조직학적·영상학적 증거를 체계적으로 정리합니다:

• 전기생리학: TrP 부위에서 높은 빈도의 endplate noise (spontaneous quantal ACh release). α-adrenergic blocker(phentolamine)로 감소.
• 생화학: TrP milieu가 산성(pH 4–5), bradykinin, CGRP, substance P, IL-6 등 cytokine 증가 → neurogenic inflammation.
• 조직학: segmental sarcomere contraction (contraction knot), taut band.
• 영상: Ultrasound에서 hypoechoic 영역 + retrograde blood flow (허혈), MR elastography에서 stiffness 증가.

actualgyn.com

learnmuscles.com

(위 그림: Taut band와 central trigger point, contraction knot 개념. 정상 근섬유 vs. 과수축된 knot.)

3. 새로운 가설의 핵심 메커니즘

(1) Neuromuscular Junction (NMJ) 수준 피드백 실패

• Presynaptic: muscarinic M1/M2 receptor, adenosine receptor (A1/A2A), sympathetic modulation이 ACh 방출을 조절. 과부하 시 이 조절 실패 → 과도한 spontaneous ACh release.
• Postsynaptic: Ca²⁺ 유입 조절 실패.

(2) Ion Channelopathies (이온 채널병)

• Ryanodine Receptor (RyR1): sarcoplasmic reticulum(SR)에서 Ca²⁺ 방출 채널. 돌연변이(예: malignant hyperthermia 관련)로 leaky channel → 과도한 Ca²⁺ 누출 → 지속 수축.

geneticlifehacks.com

flipper.diff.org

(위 그림: RYR1 수용체와 Ca²⁺ 방출 기전. Malignant hyperthermia에서처럼 과도 Ca²⁺ 유발.)

• KATP Channel (ATP-sensitive potassium channel): 저 ATP/low pH 시 개방되어 Ca²⁺ 유입 제한, 에너지 보존. 결핍 시 hypercontraction과 빠른 피로 유발 (knockout mouse 모델 증거).

nature.com

The mitochondrial ATP-dependent potassium channel (mitoKATP) controls skeletal muscle structure and function | Cell Death & Disease

(위 그림: KATP channel 정상 vs. 결핍 상태에서의 미토콘드리아 및 근육 기능 변화.)

좌측: 정상 KATP 채널 (Normal KATP Channel)

• 강렬한 운동(Intensive exercise) → 근육 내 ATP 수준 저하.
• KATP 채널이 열림(open) → 세포 내 칼슘 농도([Ca²⁺]c) 감소.
• 액틴-미오신(Actin-myosin) 교차결합(crossbridging)이 해제 → 근육 이완(relaxation).

→ 보호 메커니즘: 과도한 수축을 방지하고 근육을 보호합니다.

우측: KATP 결핍 또는 Knockout 마우스 (KATP deficient or knockout mouse)

두 가지 시나리오로 나뉩니다.

1. 정상 활동(Normal activity)
   • KATP 채널이 없거나 기능 이상 → 정상적인 액틴-미오신 교차결합과 해제가 유지됨 (큰 문제 없음).
2. 강렬한 운동(Intense exercise)
   • KATP 채널 기능 이상 → 이온 채널이 제대로 열리지 않음.
   • ATP 저하에도 불구하고 Ca²⁺가 지속적으로 세포질로 유입.
   • 액틴-미오신 교차결합이 지속(Persistent actin-myosin crossbridging) → 분절성 근절 수축(Segmental sarcomere contraction) 발생.
   • 결과: 비정상적으로 빠른 근육 피로(abnormally rapid onset of muscle fatigue)와 국소 과수축(hypercontracted sarcomeres) 발생.

핵심 의미 (한 줄 요약)

KATP 채널은 강렬한 운동으로 ATP가 떨어질 때 열리면서 세포 내 칼슘 과유입을 막아 근육 과수축과 빠른 피로를 방지하는 중요한 보호 장치입니다. 이 채널이 결핍되거나 기능이 저하되면 지속적인 국소 근절 수축(segmental sarcomere contraction)이 일어나 근막통증유발점(Trigger Point) 형성의 중요한 원인이 될 수 있습니다

(3) Sympathetic Nervous System 역할

Pre- and postsynaptic α/β-adrenergic modulation이 ACh와 Ca²⁺를 조절. TrP에서 sympathetic hyperactivity가 악순환을 유지.

(4) Muscle Fatigue와의 연계

강한 운동 시 Na⁺/K⁺-ATPase 억제, ATP 저하 → depolarization → Ca²⁺ dysregulation → 보호 기전 실패.

4. 전체 병태생리 Cascade (통합 모델)

근육 과부하/피로 → 보호 피드백 (ACh 조절, Ca²⁺ 조절, KATP 등) 실패 또는 channelopathy → 과도 ACh release 또는 cytosolic Ca²⁺ ↑ → 지속 actin-myosin cross-bridge → contraction knot + taut band → 국소 허혈, 산증, cytokine/ neuropeptide 방출 → nociceptor 활성화 + neurogenic inflammation → TrP 형성 및 referred pain, weakness, fatigue.

이 과정은 중심 감작(central sensitization)으로 이어질 수 있습니다.

Int J Mol Sci

. 2023 May 2;24(9):8142. doi: 10.3390/ijms24098142

A New Unified Theory of Trigger Point Formation: Failure of Pre- and Post-Synaptic Feedback Control Mechanisms

Robert D Gerwin 1

Editor: Irmgard Tegeder1

• Author information
• Article notes
• Copyright and License information

PMCID: PMC10179372  PMID: 37175845

Abstract

The origin of the myofascial trigger point (TrP), an anomalous locus in muscle, has never been well-described. A new trigger point hypothesis (the new hypothesis) presented here addresses this lack. The new hypothesis is based on the concept that existing myoprotective feedback mechanisms that respond to muscle overactivity, low levels of adenosine triphosphate, (ATP) or a low pH, fail to protect muscle in certain circumstances, such as intense muscle activity, resulting in an abnormal accumulation of intracellular Ca2+, persistent actin-myosin cross bridging, and then activation of the nociceptive system, resulting in the formation of a trigger point. The relevant protective feedback mechanisms include pre- and postsynaptic sympathetic nervous system modulation, modulators of acetylcholine release at the neuromuscular junction, and mutations/variants or post-translational functional alterations in either of two ion channelopathies, the ryanodine receptor and the potassium-ATP ion channel, both of which exist in multiple mutation states that up- or downregulate ion channel function. The concepts that are central to the origin of at least some TrPs are the failure of protective feedback mechanisms and/or of certain ion channelopathies that are new concepts in relation to myofascial trigger points.

초록

근막 통증 유발점(myofascial trigger point, TrP)은

근육 내 이상 부위로,

그 기원이 지금까지 제대로 설명된 적이 없다.

본 논문에서 제시하는 새로운 유발점 가설(new trigger point hypothesis)은

이 공백을 메우고자 한다.

이 새로운 가설은

근육 과활동,

아데노신 삼인산(ATP) 저하 또는

낮은 pH에 반응하는 기존의 근육 보호 피드백 기전이

특정 상황(예: 강렬한 근육 활동)에서 근육을 보호하지 못한다는 개념에 기반한다.

그 결과

세포 내 Ca²⁺가 비정상적으로 축적되고,

지속적인 액틴-미오신 교차결합이 발생하며,

통각계가 활성화되어

결국 통증 유발점이 형성된다.

관련 보호 피드백 기전으로는

신경근 접합부에서 아세틸콜린 방출을 조절하는 전신경 및 후신경 교감신경계 조절 기전, 그리고

두 가지 이온 채널병(ryanodine 수용체와 칼륨-ATP 이온 채널)의 돌연변이/변이 또는 번역 후 기능적 변화가 포함된다.

이 두 채널은

이온 채널 기능을 상향 또는 하향 조절하는 여러 돌연변이 상태로 존재한다.

적어도 일부 유발점의 기원에 핵심적인 개념은

보호 피드백 기전의 실패와/또는 특정 이온 채널병인데,

이는 근막 유발점과 관련하여 기존 문헌에 없었던 새로운 개념이다.

Keywords: feedback mechanism, myofascial pain syndrome, sympathetic nervous system, trigger points, ion channelopathy, neuromuscular junction, acetylcholine, excitation–contraction coupling

1. Introduction

The myofascial trigger point (TrP), considered to be the underlying cause of myofascial pain syndromes, was described by Travell and Rinzler in 1946 [1]. It has been increasingly studied since, despite a controversy over its existence [2]. Clinical presentations and management regimens are well-represented in the literature, but there has been little or no discussion of its origin. This paper proposes a new hypothesis of trigger point formation, one that has not appeared in the literature previously. It is acknowledged that there may be multiple causes for TrP formation [3], all leading to a same result, the TrP, and that the mechanisms proposed here may apply only to a subset of TrPs.

The specific mechanisms by which the TrP develops remains unknown despite descriptions of mechanical and physiologic stresses that are predisposed to and maintain the TrP, such as the perpetuating factors identified by Travell and Simons [4]. Simons proposed an integrated TrP hypothesis that implicated an energy crisis as a major factor causing TrPs. His hypothesis, based on (1) the absence of motor action potentials, (2) the activation of TrPs by muscle overload, (3) nociceptor activation, and (4) the therapeutic effect of stretching, postulated an overactive neuromuscular junction (NMJ) that releases excessive acetylcholine (ACh) in response to muscle overload ([4] pp. 68–79). He further postulated that the capillary compression from TrPs leads to ischemia and an inability to replenish adenosine triphosphate (ATP) that prevents the reuptake of Ca2+ from the muscle cytosol, resulting in persistent muscle sarcomere contractions. The integrated hypothesis of Simon, useful as it was, did not in fact address the actual mechanisms by which the TrP is formed. It did not account for the many regulatory mechanisms that protect muscle from injury. Even the updated versions of Simons’ integrated hypothesis left the actual origin of the TrP as a ‘black box’ mystery [5,6]. The new hypothesis proposed here is based on physiologic mechanisms that could play a role in the genesis of the TrP in at least a subset of cases. The new hypothesis is derived from a review of the current literature. It proposes that there is a failure of protective regulatory mechanisms, many of them feedback mechanisms, that prevent excessive muscle activity or that prevent a potentially injurious accumulation of Ca2+ within the muscle cytosol and offers specific examples to support the hypothesis. The new hypothesis relates these mechanisms to the development of the TrP in a way that has not been described in the literature before. It is offered as a means of stimulating research into the physiology of TrP formation and has implications for the nature of unusual fatigue and weakness in muscles with TrPs, as well as treatment implications.

Myofascial TrPs were described about 75 years ago in a paper on non-cardiac chest pains [1], though there were descriptions of similar phenomena prior to that time. Subsequent publications described referred to pain patterns and the effect of manual or invasive therapy (dry needling or TrP injection). Early histopathological reports of muscle hardening or myogelosis in TrP regions found focal areas of swelling in muscle [7,8,9,10]. Electrophysiologic studies of the TrP began to be published in the 1990s [11,12,13]. A microanalytic technique that explored the extracellular biochemical milieu of the TrP opened a new means of investigation [14]. TrP imaging, long an elusive goal, is accomplished by magnetic resonance elastography [15] and high-definition ultrasound [16]. Histopathological studies of TrPs in humans remains sparse but suggests that segmental sarcomere contraction occurs at the TrP or in adjacent taut bands (TB) [17,18].

1. 서론

근막 통증 증후군의 근본 원인으로 여겨지는

근막 통증 유발점(myofascial trigger point, TrP)은

1946년 Travell과 Rinzler에 의해 처음 기술되었다[1].

이후 논란이 지속되었음에도[2]

점점 더 많은 연구가 이루어지고 있다.

임상 양상과 치료법은

문헌에 잘 정리되어 있지만,

그 기원에 대한 논의는 거의 없었다.

본 논문은

문헌에 이전에 등장하지 않았던 통증 유발점 형성에 대한 새로운 가설을 제안한다.

유발점 형성에는 여러 원인이 있을 수 있으며[3],

모두 동일한 결과인 유발점으로 이어질 수 있고,

여기서 제안하는 기전은 유발점의 일부 아형에만 적용될 수 있음을 인정한다.

유발점이 어떻게 발생하는지에 대한 구체적인 기전은 아직 알려지지 않았다.

Travell과 Simons가

지적한 지속인자(perpetuating factors)와 같은

기계적·생리적 스트레스가 유발점을 유발하고 유지하는 것으로 알려져 있으나[4],

그 발생 기전에 대해서는 논의가 부족했다.

Simons는

통합 유발점 가설(integrated TrP hypothesis)을 제시하였는데,

여기서 에너지 위기(energy crisis)가 유발점의 주요 원인이라고 보았다.

그의 가설은

(1) 운동 활동 전위의 부재,

(2) 근육 과부하에 의한 유발점 활성화,

(3) 통각 수용체 활성화,

(4) 스트레칭의 치료 효과를 근거로 하여,

근육 과부하 시 과도한 아세틸콜린(ACh)을 방출하는 과활성 신경근 접합부(overactive neuromuscular junction)를 가정하였다

([4] pp. 68–79).

또한 유발점으로 인한 모세혈관 압박이 허혈을 유발하고

ATP를 보충하지 못하게 하여

세포질로부터 Ca²⁺ 재흡수를 방해함으로써 지속적인

근육 육아근 수축이 일어난다고 보았다.

Simons의 통합 가설은 유용했으나,

실제로 유발점이 어떻게 형성되는지에 대한 기전을 설명하지 못했다.

근육 손상을 방지하는 수많은 조절 기전을 고려하지 않았으며,

이후 업데이트된 버전에서도 유발점의 실제 기원은 여전히 ‘블랙박스’ 미스터리로 남아 있었다[5,6].

본 논문에서 제안하는 새로운 가설은

적어도 일부 유발점의 발생에 관여할 수 있는 생리학적 기전에 기반한다.

이 가설은

최신 문헌 검토를 통해 도출되었으며,

과도한 근육 활동을 막거나

근육 세포질 내 Ca²⁺의 잠재적으로 해로운 축적을 방지하는

보호 조절 기전(대부분 피드백 기전)의 실패를 핵심으로 한다.

가설을 뒷받침하는 구체적인 예를 제시한다.

이 새로운 가설은

기존 문헌에서 기술되지 않은 방식으로 이러한 기전을 유발점 발생과 연관지으며,

유발점 형성의 생리학 연구를 자극하고,

유발점이 있는 근육에서 나타나는 비정상적인 피로와 근력 저하의 본질,

그리고 치료적 함의에 대한 시사점을 제공한다.

근막 유발점은

약 75년 전 비심장성 흉통에 관한 논문에서 처음 기술되었다[1].

그 이전에도

유사한 현상에 대한 기술이 있었다.

이후의 출판물들은

방사통 패턴과 수기요법 또는 침습적 치료(건식 침술 또는 유발점 주사)의 효과를 다루었다.

초기 조직병리학 보고서에서는

유발점 부위의 근육 경화 또는 근겔증(myogelosis)에서 국소적인 부종이 관찰되었다[7,8,9,10].

유발점에 대한 전기생리학적 연구는 1990년대부터 발표되기 시작했다[11,12,13]. 유발점의 세포외 생화학적 미세환경을 탐색하는 미세분석 기법이 새로운 연구 수단을 열었다[14]. 오랫동안 어려웠던 유발점 영상화는 자기공명 탄성영상(magnetic resonance elastography)[15]과 고해상도 초음파[16]로 가능해졌다.

인간 유발점에 대한 조직병리학 연구는 여전히 부족하지만, 유발점 또는 인접한 긴장대(taut band)에서 분절적인 육아근 수축(segmental sarcomere contraction)이 발생한다는 것을 시사한다[17,18].

2. Trigger Point Physiology

This section summarizes the present body of evidence for TrP physiology, imaging, and structure, and suggests some implications of the findings (Table 1).

2.1. Electrophysiology

Normal resting muscle is relatively electrically quiet. Miniature endplate potentials (MEPPs) occur at a frequency of 1–6 per second and endplate spikes occur in resting muscle [19,20]. In contrast to resting muscle, the electromyogram (EMG) of the TrP shows a persistent, low amplitude (5–50 µV), high frequency activity that looks like high frequency MEPPs punctuated by intermittent, higher amplitude (100–600 µV), that are initially negative, biphasic, endplate spikes [13]. Resting TrP EMG activity, termed endplate noise (EPN), may be as much as two to three orders of magnitude faster than normal MEPP frequency. EPN indicates that there is an excess of ACh molecules at the NMJ endplate zone in TrPs compared to normal resting muscle, suggesting that there might be a failure of the feedback mechanisms that regulate the release of ACh from the MNT. Alpha-adrenergic inhibitors and botulinum toxin both reduce EPN activity [12,13,21], indicating that EPN is the result of ACh released from presynaptic vesicles.

2.1. 전기생리학

정상적인 휴지기 근육은 전기적으로 비교적 조용하다. 미세 종판 전위(miniature endplate potentials, MEPPs)는 초당 1~6회 발생하며, 휴지기 근육에서도 종판 스파이크가 나타난다[19,20]. 이에 비해 유발점의 근전도(EMG)에서는 지속적인 저진폭(5~50 µV), 고주파 활동이 관찰되며, 이는 정상적인 고주파 MEPP처럼 보이고, 간헐적으로 더 높은 진폭(100~600 µV)의 초기 음성, 이상성(biphasic) 종판 스파이크가 섞여 있다[13]. 휴지기 유발점의 EMG 활동(종판 소음, endplate noise, EPN)은 정상 MEPP 빈도보다 2~3차수 정도 빠를 수 있다. EPN은 유발점의 신경근 접합부 종판 부위에 정상 휴지기 근육보다 과도한 ACh 분자가 존재함을 나타내며, 이는 운동 신경 말단(MNT)으로부터 ACh 방출을 조절하는 피드백 기전의 실패 가능성을 시사한다. α-아드레날린 차단제와 보툴리눔 독소는 모두 EPN 활동을 감소시킨다[12,13,21]. 이는 EPN이 시냅스전 소포로부터 방출된 ACh의 결과임을 보여준다.

2.2. Sympathetic Nerve Inhibition of TrP EPN

The ⍺-adrenergic inhibitor phentolamine reduces the average integrated signal of EPN by about 60% [13], but the specific mechanism by which this occurs has not been previously addressed. Both the ⍺- and β-sympathetic nervous systems play a role in modulating muscle contraction, as will be discussed subsequently.

2.2. 교감신경에 의한 유발점 EPN 억제

α-아드레날린 차단제인 펜톨아민(phentolamine)은 EPN의 평균 통합 신호를 약 60% 감소시킨다[13]. 그러나 이 현상이 일어나는 구체적인 기전은 이전에 다루어지지 않았다. α- 및 β-교감신경계는 모두 근육 수축을 조절하는 역할을 하며, 이에 대해서는 뒤에서 논의할 것이다.

2.3. Biochemical Pathophysiology

The TrP extracellular milieu is acidic (pH in the range of 4–5, below the normal range of 7.35–7.45) and has elevated levels of cytokines and neurotransmitters, such as IL-6, bradykinin, substance P, and calcitonin-gene-related-peptide (CGRP) compared to non-trigger point regions [14]. The acidic pH suggests that the TrP region is hypoxic and ischemic [20]. An acid extracellular milieu can inhibit acetylcholinesterase (AChE), and therefore can contribute to an increase in the concentration of ACh molecules at the motor endplate. CGRP can increase the quantal size of ACh released from the motor nerve terminal [22] and can upregulate nicotinic ACh receptors (nAChRs) at the motor endplate region, thereby expanding the AChR zone [23]. Thus, CGRP co-released with ACh from the MNT has the effect of increasing the number of ACh molecules at the motor end plate [24]. The CGRP effect at the NMJ is delayed, though not immediately, but it could be an upstream initiating event contributing to the development of the TrP.

Neurotransmitters and cytokines present in high concentration in the extracellular TrP milieu, such as substance P and CGRP may also produce neurogenic edema. The hypoechoic appearance of the TB on high-definition ultrasound is consistent with neurogenic edema, although there are other explanations for the nodular swelling at the TrP, including the recent finding of glycosaminoglycans surrounding contraction knots in an experimental TrP paradigm [25,26,27,28,29]. These possible causes of the stiffened taut band differ from the long-held idea that the taut band is the result of multiple short loci of contracted sarcomeres alternating with long zones of stretched sarcomeres.

2.3. 생화학적 병태생리

유발점의 세포외 미세환경은 산성(pH 4~5 범위, 정상 범위 7.35~7.45보다 낮음)이며, 비유발점 부위에 비해 IL-6, 브라디키닌, 물질 P, 칼시토닌 유전자 관련 펩티드(CGRP) 등 사이토카인과 신경전달물질 수치가 증가해 있다[14]. 산성 환경은 유발점 부위가 저산소증(hypoxic)과 허혈(ischemic) 상태임을 시사한다[20]. 산성 세포외 환경은 아세틸콜린에스터라제(acetylcholinesterase, AChE)를 억제하여 운동 종판 부위의 ACh 농도를 증가시킬 수 있다. CGRP는 운동 신경 말단에서 방출되는 ACh의 양(퀀탈 크기)을 증가시키고[22], 운동 종판 부위의 니코틴성 ACh 수용체(nAChR)를 상향 조절하여 AChR 영역을 확대한다[23]. 따라서 ACh와 함께 공동 방출되는 CGRP는 운동 종판 부위의 ACh 분자 수를 증가시키는 효과가 있다[24]. CGRP의 NMJ 효과는 즉각적이지 않고 지연되지만, 유발점 발생에 기여하는 상위(upstream) 개시 사건일 수 있다.

유발점 세포외 미세환경에 고농도로 존재하는 신경전달물질과 사이토카인(물질 P, CGRP 등)은 신경인성 부종(neurogenic edema)을 유발할 수도 있다. 고해상도 초음파에서 긴장대(TB)가 저에코(hypoechoic)로 나타나는 것은 신경인성 부종과 일치하지만, 유발점의 결절성 부종에는 다른 설명도 가능하다. 예를 들어 최근 실험적 유발점 모델에서 수축 매듭 주변에 글리코사미노글리칸(glycosaminoglycans)이 존재한다는 발견이 있다[25,26,27,28,29]. 이러한 긴장대 경화의 가능한 원인들은 오랫동안 믿어져 온 “여러 개의 짧은 수축된 육아근 부위와 길게 늘어난 육아근 부위가 교대로 존재한다”는 기존 가설과 다르다.

2.4. Histopathological Evidence

Segmental sarcomere contraction was found retrospectively in one canine skeletal muscle specimen obtained by open biopsy from a taut band [18], and has been reported in one study of human trapezius muscle obtained by needle biopsy of a TrP region [17] performed for a study of other aspects of muscle morphology. The term ‘contraction knots’ has been used both to describe the regions of segmental sarcomere contraction and the palpable nodular hardness found within the TB ([4] pp. 67–69).

Segmental sarcomere contraction has been reported in two different animal models designed to replicate the TrP phenomenon [27,28,29]. One model utilized blunt trauma to the muscle followed by intensive exercise. The other used AChE inhibitors to induce segmental sarcomere shortening and other TrP phenomena. In addition, muscle fiber super-contraction associated with large intracellular increases in unstimulated Ca2+ was found in KATP-deficient mouse flexor digitorum brevis single muscle fibers that were exercised to fatigue [30].

Sarcomere hypercontraction can be seen as an artifact in percutaneous muscle biopsy specimens, but this artifact does not occur when the specimens are treated with osmolarity-corrected glutaraldehyde [31], as was carried out in the study reporting on segmental sarcomere contraction in humans [17]. Anesthetics, such as lidocaine and bupivacaine can result in muscle degeneration and hypercontraction. Open biopsies are generally length-fixed and do not show segmental hypercontraction. The segmental hypercontraction in the human biopsy material cited above [17] was seen on material obtained by large bore needle biopsy, but was present both in light microscopic sections and on electron microscopy, the latter was seen in tissue fixed with osmolarity-controlled glutaraldehyde. Segmental sarcomere hypercontraction was also found in a skeletal muscle subjected to eccentrically challenged, unloaded rat adductor longus muscle [32], muscle subjected to repetitive eccentric contractions [33], and in muscle subjected to contraction and tension loading [34,35], studied both by light and electron microscopy.

2.4. 조직병리학적 증거

긴장대에서 채취한 개의 골격근 표본(개방 생검)에서 분절적 육아근 수축(segmental sarcomere contraction)이 후향적으로 발견되었고[18], 인간 승모근(trapezius)에서 유발점 부위를 바늘 생검으로 얻은 표본에서도 분절적 수축이 보고되었다[17]. ‘수축 매듭(contraction knots)’이라는 용어는 분절적 육아근 수축 부위를 가리키는 동시에 긴장대 내에서 만져지는 결절성 경결을 의미하기도 한다([4] pp. 67–69).

분절적 육아근 수축은 유발점 현상을 재현하기 위해 설계된 두 가지 동물 모델에서도 보고되었다[27,28,29]. 한 모델은 근육에 둔상을 가한 후 강도 높은 운동을 시켰고, 다른 모델은 AChE 억제제를 사용하여 분절적 육아근 단축과 기타 유발점 현상을 유도하였다. 또한 KATP 결핍 마우스의 단일 근섬유(flexor digitorum brevis)를 피로 운동시켰을 때, 자극되지 않은 상태에서 세포 내 Ca²⁺가 크게 증가하면서 근섬유 과수축(super-contraction)이 관찰되었다[30].

경피적 근육 생검 표본에서는 육아근 과수축이 인공물(artifact)로 나타날 수 있으나, 삼투압 보정된 글루타르알데히드로 처리하면 이러한 인공물이 발생하지 않는다[31]. 위에서 인용한 인간 연구[17]에서도 삼투압 조절 글루타르알데히드로 고정된 조직에서 분절적 과수축이 관찰되었다. 리도카인, 부피바카인 등의 마취제는 근육 변성과 과수축을 유발할 수 있다. 개방 생검은 일반적으로 길이가 고정되어 분절적 과수축이 나타나지 않는다. 그러나 위 인간 바늘 생검 표본에서는 광학현미경과 전자현미경 모두에서 분절적 육아근 과수축이 확인되었다.

분절적 육아근 과수축은 편심 부하를 받은 쥐 내전근(adductor longus)[32], 반복적인 편심 수축을 받은 근육[33], 수축과 장력 부하를 받은 근육[34,35]에서도 광학현미경과 전자현미경으로 관찰되었다.

2.5. Ultrasound Imaging of Trigger Points

Trigger points and TBs appear as hypoechoic regions on ultrasound, with retrograde blood flow seen in the TrP region itself, consistent with ischemia and consequent hypoxia [16].

2.5. 유발점의 초음파 영상

유발점과 긴장대는 초음파에서 저에코(hypoechoic) 영역으로 나타나며, 유발점 부위 자체에서 역행성 혈류(retrograde blood flow)가 관찰된다. 이는 허혈과 그로 인한 저산소증과 일치한다[16].

Table 1.

Objective laboratory features and subjective clinical signs of the trigger point upon which the new hypothesis is based. Specificity and sensitivity levels under physical examination are estimates, not from studies.

FeatureDescriptionReferencesLevel of Confidence

Electrophysiology	High frequency, low voltage endplate noise, attenuated by ⍺-adrenergic inhibitors and by botulinum toxin. Eighteen rabbits, 10 received one dose of botulinum toxinTx, 10 received multiple doses of botulinum toxin. Ten were controls. Endplate noise was diminished in all rabbits that received BTx, but not in the control rabbits [21]. Spontaneous electrical activity was found in TrPs of 29 tension headache patients, 25 fibromyalgia patients, but in none of the eight controls [11]. Phentolamine IV injection vs control injection of saline in nine rabbits. Twenty-five active trigger spot loci were sampled. Mean average integrated signal of spontaneous electrical activity was reduced from 9.89 µV to 9.92 µV (p < 0.05) [13].	[11,13,21]	High
Histopathology	Segmental sarcomere contraction. 1.32 female office workers, 15 myalgic, and 15 no pain. Taut bands were found in all subjects. Sarcomere compression in five non-myaglic and two myalgic subjects on limited tissue saved from a prior study [17]. 1. Canine taut band study, 10 animals, one example identified retrospectively [20]. 2.	[17,20,23,29]	Probable, not proven
Microanalytic biochemistry	Acidic (low pH); elevated levels of certain neurotransmitters and cytokines. Study of humans with neck pain. Three controls (three latent TrPs, 3 active TrPs, no neck pain, and no TrP). Significantly elevated levels of the following in the active TrP neck pain group (p < 0.01): protons, BDKN, CGRP, Subs P, TNF-alpha, IL-1 beta, 5-HT, NE.	[14]	Highly likely; needs confirmation from a second laboratory
Ultrasound imaging	Nine subjects (seven women), 13 active TrP sites and nine latent TrPs sites. Fourteen normal in trapezius muscles; findings: focal, hypoechoic regions on 2D US and focal regions of reduced vibration amplitude on VSE indicating a localized, stiff nodule.	[16]	High
Magnetic Resonance Elastography	Proof of concept pilot trial on two female subjects showed taut bands that are detectable and quantifiable with MRE imaging. The findings in the subjects suggest that the stiffness of the taut bands (9.0+/−0.9 KPa) may be 50% greater than that of the surrounding muscle tissue.	[15]	High
Physical examination	Taut band, nodular region of tenderness, reproduction of usual pain; high specificity because a tender nodule on a taut band defines a trigger point. The outcome of the physical examination of trigger points remains controversial.	[4]	Moderate for diagnostic purposes; high specificity, moderate sensitivity
Physical examination	Non-wasting weakness of muscle rapidly reversed after trigger point inactivation, highly specific because improvement after release of a trigger point defines a trigger point effect. There are no studies eval‎uating this response.	[4]	N/A; moderate sensitivity, highly specific
History	Onset is often preceded by acute or repetitive muscle overuse.	[4,6]	n/a

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Abbreviations: TrP trigger point; BDKN bradykinin; CGRP calcitonin gene-related peptide; Subs P substance P; 5-HT serotonin; NE norepinephrine; US ultrasound; VSE vibration sonoelastography.

3. Analysis of Elements Related to the New Trigger Point Hypothesis3.1. The New Trigger Point Hypothesis

The new trigger point hypothesis proposes that in a subset of cases, the failure of protective feedback mechanisms results in a cascade of events following intensive, acute, events, such as trauma, or following chronic, repetitive, fatiguing muscle activity, resulting in the formation of TrPs. The postulated dysfunctional feedback mechanisms include those that regulate the release of spontaneous non-evoked quantal ACh at the NMJ that induce miniature endplate potentials and those that modulate the release of ionized calcium into the muscle cell, that results in the binding of actin to myosin, leading to sarcomere contraction. The new hypothesis postulates that these mechanisms fail either because they are overwhelmed to the point that feedback controls no longer respond or are insufficient, or because of up- or downregulating mutations/variants in the molecular subunits of key ion-channels that control the intracellular concentration of Ca2+, such as the ryanodine receptor (RyR) and the potassium-ATP (KATP) ion channel, or post-translational changes that cause ‘leaky’ ion channels. Specifically, the regulatory mechanisms of interest include (1) the presynaptic ionotropic nAChR ion channels and the metabotropic muscarinic M1 and M2 receptors that modulate the release of ACh molecules into the synaptic space, and (2) the postsynaptic ionotropic potassium and sodium channels that control the influx of Ca2+ into the muscle cytosol. In addition, there is feedback from ACh released into the synaptic space that inhibits the presynaptic ACh release from the MNT [36] and postsynaptic activation of nAChRs that modulate ACh through a transsynaptic feedback loop. Thus, there are multiple feedback mechanisms that limit the release of ACh into the synaptic space and prevent excessively high-frequency motor unit action potentials that could overwhelm the adenosine triphosphate (ATP)-requiring calcium reuptake processes, or that could result in excessive muscle work to the point of fatigue and the development of TrPs ([4] p. 19).

Lengthening eccentric muscle contraction is an example of muscle overload that causes muscle injury [37,38,39,40,41] and/or TrPs, though the latter outcome remains unproven.

Muscle fatigue is such a dogma of TrP initiation among clinicians, that a deep understanding of the physiology of skeletal muscle fatigue would be very useful to the understanding of the origin of the TrP.

Causes of the TrP are likely multifactorial, and muscle fatigue is likely but one cause. Many factors can contribute to the vulnerability of muscle to become fatigued or to develop TrPs. One potential factor is an ineffective KATP ion channel. Mice with non-functioning KATP ion channels develop loci of hypercontracted sarcomeres during fatiguing exercise and have a faster rate of fatigue than animals with normal KATP ion channels [42]. However, their vulnerability to develop TrPs has never been examined.

3.2. Failure to Control Quantal ACh Release Leading to Endplate Noise

Endplate noise is a long-lasting phenomenon in TrPs, characterized by low amplitude, extremely high-frequency, and electrical activity in the resting state. It is indicative of an unusually high concentration of ACh at the motor endplate. ACh is released from the MNT in three different ways: (1) evoked quantal release, (2) spontaneous quantal release, and (3) spontaneous non-quantal release [43]. Evoked quantal release occurs following an efferent nerve impulse that results in a motor action potential, clearly not the case in resting muscle. Spontaneous non-quantal release (NQR) of ACh makes up 90–98% of the resting muscle total release of ACh and about half of that is from motor nerve endings. The NQR of ACh results in postsynaptic concentrations that are too low to evoke membrane responses unless AChE is inhibited [44], but can hyperpolarize the postsynaptic membrane [43]. It is independent of quantal release, and it can cause the depolarization of the postsynaptic membrane, as seen by occasional MEPPS [20]. It is an unlikely candidate for the cause of EPN because of its low concentration and because an MEPP is most commonly caused by the release of a single quantum of ACh [20]. Additionally, the depression of EPN activity by botulinum toxin strongly indicates that ACh is released from intracellular vesicles [21] rather than from leakage. Therefore, the most likely cause of EPN at the TrP is spontaneous quantal release (SQR) that occurs at rest. Spontaneous quantal release can cause subthreshold membrane depolarization that induces segmental sarcomere contraction both in skeletal and cardiac muscle [45]. Inhibition of AChE in the motor endplate zone, and expansion of AChRs beyond the motor endplate zone have an amplification effect of increasing ACh at the endplate, resulting in subthreshold membrane depolarization or a fully propagated motor action potential.

An animal model of TrPs created by blunt trauma to muscle followed by intensive exercise showed elevated ACh content and lowered AChE at the TrP spot, but the spontaneous electrical activity in their model consisted of positive sharp waves, fibrillation potentials, and fasciculation potentials [28], characteristic of denervation, rather than of TrPs.

Noncanonical signaling in which the nAChR itself is the signaling molecule [46] mediates changes in the quantal content of ACh. This modulatory mechanism of regulating changes in quantal content should increase the release of ACh molecules in response to blocking nAChRs. This has not been examined in TrP models.

3.3. Sympathetic Nervous System Contribution

The ⍺-adrenergic sympathetic nervous system (SNS) plays a major role in upregulating the effect of ACh at the NMJ in TrPs, as shown by the inhibiting effect of ⍺-adrenergic inhibitors, such as phentolamine on EPN. It achieves this either by increasing the release of ACh from the MNT or by otherwise increasing the concentration of ACh molecules at the motor endplate. The SNS innervates skeletal muscle and the NMJ both pre- and postsynaptically [47,48,49]. Elimination of the SNS influence on skeletal muscle by sympathectomy results in a decrease in MEPP frequency and amplitude by a presynaptic decrease in the quantal release of ACh, a reduction in the complexity of the NMJ, and postsynaptically, a reduction in the number of AChRs. Sympathomimetic drugs, such as epinephrine and norepinephrine reverse the effects of sympathectomy and improve NMJ transmission. Epinephrine and norepinephrine both decrease the spontaneous release of ACh quanta, an effect blocked by ⍺-adrenergic inhibitors in the case of epinephrine [49] and β-adrenergic inhibitors in the case of norepinephrine [50]. Alpha-2 agonists increase the MEPP frequency, an action blocked by the ⍺-adrenergic inhibitors phentolamine, prazosin, and yohimbe, indicating that the effect is presynaptic [51]. Synchronization of ACh release increases the likelihood of producing an action potential, an effect blocked by both alpha-2 and beta-2 agonists [45]. Epinephrine and other sympathomimetic agents modulate ACh quantal release via presynaptic P/Q calcium channels, and via N-type calcium channels postsynaptically to modulate intracellular [Ca2+]c. Β-adrenergic agonists act postsynaptically to enhance muscle contraction force. The SNS also acts indirectly postsynaptically via G-protein ⍺i2 and other genes to regulate intracellular [Ca2+]c [47,48].

3.4. Adenosine Receptor Interaction with Muscarinic Receptors

Adenosine receptors A1 and A2A at the MNT interact with M1 and M2 muscarinic receptors to regulate ACh through a feedback mechanism that responds to the frequency of action potential discharges at the NMJ and to levels of ATP and adenosine [51,52]. This mechanism serves as a detector of low concentrations of ATP associated with intense muscle activity. ATP concentration is higher at lower frequencies of membrane depolarization and lower at higher frequencies. The M1 faciliatory receptor is activated at lower concentrations of ACh with lower frequencies of firing, but higher concentrations of ACh associated with high frequency discharges activates inhibitory M2 receptors via A2A-adenosine receptors [53]. This is a protective mechanism that could limit the depletion of ATP that could impair intracellular Ca2+ reuptake at higher frequencies of motor action potentials.

3.5. Summary of Sympathetic Nervous System Effects

The SNS acts presynaptically to modulate the spontaneous ACh quantal release through the action of catecholamines. Quantal release is further modulated by the interaction of adenosine receptors A1 and A2A with muscarinic receptors M1 and M2. Postsynaptic modulation of excitation–contraction coupling includes G-protein second messenger and protein kinase C pathways that regulate calcium influx into the muscle cytosol.

3.6. Brain-Derived Neurotrophic Factor

Brain-derived neurotrophic factor (BDNF) acts presynaptically to modulate ACh quantal release via protein kinase C pathways, regulated by a feedback control mechanism related to evoke (efferent nerve stimulation) muscle contraction [54]. The studies of BDNF in muscle pain have mostly been directed towards its role in nociception [55,56,57].

3.7. Muscle Fatigue

Muscle fatigue from intensive or repetitive muscle action may initiate a TrP that can persist after the initiating event. Muscle fatigue can involve multiple pathways involving muscle, but two systems of potentially particular relevance to TrPs and fatigue or weakness associated with TrPs will be discussed. The evoked quantal release of ACh leads to the process of excitation–contraction coupling, whereby the release of a neurotransmitter (ACh) is converted to an electrical signal through membrane depolarization and then to a mechanical act, muscle contraction. Membrane depolarization causes an electrical impulse to travel through the transverse t-tubule, resulting in the dephosphoralization of the dihydropyridine (DHPR) ion channel that then activates the RyR1 ion channel and releases Ca2+ from the sarcoplasmic reticulum (SR) into the muscle cytosol, where Ca2+ binds with troponin to initiate actin-myosin cross bridging and muscle contraction. Factors that affect the force and duration of muscle contraction and produce fatigue include those that lead to a motor unit action potential and those that modulate the level of intracellular Ca2+.

Muscle fatigue occurs after high intensity exercise. The time after one action potential is generated before a second action potential can be generated is prolonged in in vivo muscle contractions-to-fatigue studies under partially depolarized conditions in rat fast twitch skeletal muscle [58]. This phenomenon, called reprime time, is dependent on a membrane repolarization greater than −65 mV. Based on observations that muscle contractions can increase S-glutathionylation of Na+-K+-ATPase, disulfide was added between glutathione and oxidized cysteine residues, an action that can be mediated by reactive oxygen species. This inhibits Na+-K+-ATPase activity in the t-tubule system, essential for the maintenance of the Na+ and K+ electrochemical gradients during and after high intensity contractions. However, intense muscle activity also phosphorylates phospholemman (PLM) and dissociates it from Na+-K+-ATPase, which otherwise suppresses its activity. The effect of PLM dissociation from Na+-K+-ATPase is an increase in its activity. The two effects of intense muscle contraction balance each other, maintaining membrane gradient stability. However, when ATP levels are low, S-glutathionylation of Na+-K+-ATPase occurs, as in intense muscle activity, a persisting effect after fatiguing muscle stimulation. The increased inhibition of Na+-K+-ATPase could contribute to a decrease in t-tubule excitability, that along with lowered ATP levels, would cause a decrease in the force of muscle contraction. In fact, ATP levels can fall quite low after exercise [59]. An alternative explanation for a decreased Na+-K+-ATPase is that it is the result of lowered glycogen levels in muscle after muscle contraction, as ATP is generated via the glycolytic pathway [60]. A longer repriming period is in fact related to decreased Na+-K+-ATPase activity [61]. The fatigue rate is faster in KATP-ion channel-deficient muscle fibers than in normal fibers, despite the fact that KATP-ion channel opening increases with the rate of fatigue [30], so that it might be expected that the absence of KATP ion channels would not result in an altered rate of fatigue. However, the greater rate of fatigue may be due to fiber damage and contractile dysfunction in intensely exercised KATP-deficient mice [62].

3.8. Ion Channelopathy

Muscle overload (muscle activity to or beyond fatigue) is a commonly accepted, though unproven, cause of TrPs, whether acute overload or chronic and repetitive. If this is the case, perhaps even elite athletes should have TrPs. In fact, there is literature related to the treatment of athletes with TrPs; (see for example [63,64,65,66]). However, there are no epidemiological studies of TrPs in athletes, whereas there are studies of myalgia following exercise or repetitive activity. One study of trigger point morphology incidentally showed taut bands in all studied keyboard workers whether or not they had myalgia [17].

Muscle overload or intense exercise can produce muscle injury or muscle cell apoptosis from an excess of [Ca2+]c. Mechanisms that protect muscle from such cellular injury and apoptosis include the KATP ion channel opening that limits Ca2+ ingress into the muscle cytosol when intense muscle activity lowers ATP levels. Another mechanism is the ryanodine receptor (RyR) ion channel for the egress of calcium from the SR into the cytosol and the ATP-dependent sarcoplasmic reticulum calcium ATPase (SERCA) mechanism for calcium reuptake from the muscle cytosol. Each of these molecular entities is known to have multiple mutations/variants that lead to either functional up- or downregulation, or to alter other channel functions as SERCA does for the Piezo protein mechanotransduction channels [67]. Molecular subunit alleles in ion channels not only up- or downregulate channel function, but can also alter sensitivity to inhibitory factors, as happens with KATP ion in the Cantú syndrome, a rare multisystem disorder of hypertrichosis, cardiomegaly, and skeletal and other anomalies [68].

3.8.1. Ryanodine Receptor Channelopathy

The RyR regulates the influx of calcium from the intracellular SR stores into the myofibril cytosol. Ingress of calcium from the SR is accomplished largely through the RYR1 ion channel, the predominant isoform in skeletal muscle. The amount of calcium that enters and leaves the cytosol is critical, for too little ionized calcium reduces the force of muscle contraction, and too much calcium can lead to muscle cell injury or cell death. Removal of calcium from the cytosol is accomplished by the SERCA mechanism. The RyR is the largest of the known ion channels. It is a P-type gated channel that has six transmembrane regions. It opens in response to membrane depolarization, part of the excitation–contraction coupling process, and is also a calcium induced calcium channel. Membrane depolarization activates L-type voltage-gated Ca2+ DHPR channels, that otherwise physically block RyR1 channels to prevent Ca2+ transit through the receptor pore. Ca2+ in the cytosol binds to troponin, removes tropomyosin from myosin-head binding sites, allowing cross bridging with actin. Repeated binding, release, and binding allows for a progressive ‘walking’ of actin along the myosin molecule, shortening the sarcomere. RyR1 activity is modulated by many factors, including phosphorylation, oxidation, nitrosylation, and mutation. Several muscle diseases are associated with RyR1 mutations, including central core and multicore diseases, but the most relevant one for TrPs is malignant hyperthermia via a gain of function mutation.

3.8.2. Malignant Hyperthermia

Malignant hyperthermia (MH) is a genetic disorder of a potentially lethal hypermetabolic crisis associated with a rapid, uncontrolled ingress of Ca2+ into muscle cells [69]. The RyR1 gene is the key mutant allele, most often inherited as an autosomal dominant. There are over 400 mutants of the RyR1 gene, of which more than 40 are associated with MH. The genes CACNAIS and STAC3 are also associated with MH [69]. The clinical syndrome includes muscle rigidity and rhabdomyolysis. The MH mutations result in a ‘leaky’ RyR1 ion channel that results in a rapid and uncontrolled transit of Ca2+ from the SR into the cytosol, causing persistent actin-myosin cross bridging and sarcomere shortening. Ca2+ must be removed from the cytosol to reverse actin-myosin cross bridging and to allow for the muscle to relax. As the ATP essential for Ca2+ reuptake is depleted, Ca2+ reuptake fails and an excess of cytosolic Ca2+ accumulates in the cytosol, resulting in persistent actin-myosin cross bridging, tremors, contractions, and rigidity.

Phenotypic penetrance is variable and incomplete in MH. The clinical syndrome is triggered by exposure to certain substances, such as succinylcholine and halothane. RyR1 ion channel function is modulated by other substances or processes, including Ca2+, Mg2, caffeine, ATP, calmodulin, phosphorylation, and oxidation [70,71]. Arrythmias, seizures, and myopathy can occur. However, when not exposed to a trigger, the individual with the RyR1 mutation can function perfectly well and be healthy. Gene penetrance is incomplete and multiple different alleles can exist, making clinical presentation variable. Thus, the potential exists that an RyR1 allele might create a vulnerability to develop TrPs when the carrier is exposed to intense exercise or to another trigger.

3.8.3. RyR Mutation or Post-Translational Modification Causing Exercise Intolerance

That RyR1 functional variants can be relevant to TrP myofascial pain syndromes is suggested by the report of 14 individuals with exertional rhabdomyolysis or myalgia. Thirty-nine individuals who were eval‎uated had one of nine mutations or variants. Most had no or only subtle weakness. Some had affected family members as well but without rhabdomyolysis or exertional myalgia. Some were able to engage in intense exercise [72]. Remodeling of the RYR1 complex that is the major Ca2+ release channel in skeletal muscle by progressive PKA-hyperphosphorylation, S-nitrosylation, and by depletion of the RyR1 stabilizing subunit calstablin results in leaky channels that cause decreased exercise tolerance [73]. RyR1 is post-translationally modified in heart failure patients leading to pathological Ca2+ release as a potential mechanism for skeletal muscle weakness and impaired exercise tolerance [74]. Thus, it is possible that either by mutation or by post-translational modification of the RyR1 ion channel that is either genetic or secondary to intense exercise or by some other means, an individual may have significantly diminished exercise tolerance and be more vulnerable to a post-translational modification of the ion channel that would be either muscle specific or fiber-type specific.

3.8.4. ATP Dependent Channel Mutations and Muscle Function: The KATP Ion Channel (Figure 1)

The KATP ion channel opens when intense exercise lowers the concentration of ATP that is required for the maintenance of the Na+K+ pump. The Na+K+ pump is necessary for sarcolemma and t-tubular action potentials, the generation of actin-myosin cross bridging, and the SR-ATPase that powers the Ca2+ reuptake into the sarcolemma [75]. Intense muscle exercise consumes ATP, resulting in very low ATP levels [42,75]. The ATP-depleting effect of intense muscle exercise differs among muscle phenotypes and slow and fast twitch muscle fibers. ATP levels during normal activity rarely fall below 60–70% of pre-exercise levels. Muscle protective mechanisms, as described previously, prevent muscle activity from continuing at such a high intensity as to cause ATP levels to fall dangerously low. One such mechanism is the ATP-potassium channel, particularly the KATP ion channel that when open limits the influx of Ca2+ into the cell. The KATP ion channel, located in the t-tubule, serves as an energy and pH sensor. The ion channel is made of four subunits: the Kir subunits that are inwardly rectifying K+ channel-forming subunits and two sulfonylurea receptor (SUR) regulatory subunits. The subunits are gene-encoded for Kir6.1 and Kir6.2, such as the KCNJ8 gene that encodes Kir6.2, and by ATP binding cassette genes ABCC8 (SUR1) and ABCC9 (SUR2) [74]. In normal circumstances, including continuous low-level exercise, the myoprotective KATP ion channel is closed. When ATP levels fall significantly, the KATP ion channel opens. It also opens when the pH falls and when there is metabolic stress, such as ischemia and hypoxia. The result of opening the channel is the conservation of ATP. Outward K+ currents oppose inward Na+ currents that depolarize the muscle membrane when the ion channel is open, maintaining resting membrane potentials, resulting in a decreased action potential amplitude, reduced release of Ca2+ from the SR into the muscle cytosol, decreased Ca2+-ATPase activity, and therefore less ATP consumption [30,75].

In KATP knockout mice (KATP −/−) or in muscle treated with a KATP inhibitor, such as glibenclamide, the myoprotective action of KATP is absent. Under usual circumstances, such knockout mice behave normally and show normal muscle function. However, when muscles lacking KATP ion channel activity are intensively exercised to fatigue, as when muscle is subjected to high-frequency tetanic stimulation, ATP levels fall and [Ca2+]c rise. The muscle membrane becomes hyperdepolarized and muscle fibers may become super contracted [30,42,75,76]. Peak tetanic force is reduced by almost a third in KATP knockout (Kir6.2 −/−) mice compared to wild type mice. The Kir6−/− animals recover only about 2/3 of their peak tetanic force after 15 min. Thus, the Kir6−/− knockout mice are less able to tolerate intense exercise, may develop an energy crisis, and are more vulnerable to contractile dysfunction [40,75,77] (Figure 1). Verapamil significantly reduced the high levels of [Ca2+]c in these circumstances [42,77].

Figure 1.

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The KATP ion channel effect on muscle function under normal circumstances and when deficient or absent.

KATP ion channel activity is phenotype dependent and muscle specific; its activity is greater in fast twitch muscle than in slow twitch oxidative fibers that have a greater capacity to generate ATP, and that are least affected by the absence of KATP ion channels. Fast twitch glycolytic fibers are most dependent on the myoprotective effect of the KATP ion channel [74]. Rat soleus muscle is a slow twitch muscle, whereas the extensor digitorum longus (EDL) is a mixed slow and fast twitch muscle, and the rat flexor digitorum brevis is predominantly fast twitch [76]. The two fiber types are compartmentalized in the rat EDL, the medial compartment comprises primarily of slow twitch oxidative fibers and the lateral compartment of predominantly fast twitch glycolytic fiber. The medial compartment has greater fatigue resistance than the lateral compartment [77]. Thus, it is critical to understand the nature of the muscle and its fiber types when conducting studies of KATP function and of muscle fatigue.

Muscle lacking functioning KATP activity resemble TrP containing muscle in several ways. Muscle is unaffected when activity is moderate and not excessive or intensive. This is consistent with the normal human skeletal muscle function until it is overloaded or worked beyond its capacity. Not all muscles or muscle fibers are affected. In TrP affected muscle, the involvement of muscle fibers is heterogeneous, not homogeneous. Segmental sarcomere contraction may be seen in TrP regions, such as the super contraction of muscle fibers in KATP knockout mice that are subjected to muscle overload. Muscle force is eventually reduced, and the onset of fatigue is faster in knockout mice. In humans, muscles with TrPs are weaker than normal, as shown by a rapid return of normal strength after the TrP is inactivated, though the mechanism may be entirely different from that in KATP knockout mice.

4. Conclusions

The new hypothesis proposes that in at least a subset of situations in which TrPs form the initiating event is either an acute muscle overload or repetitive muscle action to fatigue in which muscle activity performed beyond the sustainable capacity of the muscle results in either an excess of ACh molecules at the motor endplate or a dangerously high concentration of Ca2+ in the muscle cytosol or both. In either case, there is a potential danger of muscle injury or damage. The new hypothesis postulates that there are feedback mechanisms both at the presynaptic and the postsynaptic levels to prevent either a consequent dangerous drop in levels of ATP or a dangerous rise in intracellular calcium levels, and that one or more of the myoprotective feedback mechanisms fail.

The new hypothesis suggests areas of productive research and potential management regimens that could be explored. For example, genetic studies of individuals with persistent or recurrent myofascial trigger point pain syndromes could identify ion channelopathies, that could lead to simple treatment measures, such as the avoidance of caffeine, or employ alpha or beta blockers, CGRP inhibitors, or modified exercise regimens. Furthermore, studies of fatiguability in TrP-containing muscles could explain some clinical features of TrPs.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The author declares no conflict of interest.

Funding Statement

This research received no external funding.

Footnotes

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References

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