Myofascial trigger points (MTrPs) are hyperirritable sites within skeletal muscle that cause local and referred pain. Their biochemical basis remains unclear. Classical models emphasize ischemia and energy depletion, while newer findings point to motor endplate hyperactivity, calcium imbalance, and local inflammation as key drivers.
A narrative review of literature from 2015–2025 (PubMed, Scopus, Web of Science) was conducted, including seminal earlier studies. Empirical and theoretical works on biochemical and molecular mechanisms of MTrPs were analyzed across five domains: endplate dysfunction, ion regulation, metabolism, inflammation, and structure.
Evidence supports excessive acetylcholine release and sustained calcium influx at the motor endplate, leading to local contraction and hypoxia. Ion channel impairment (RyR, K-ATP) perpetuates calcium overload, while metabolic stress produces acidosis and accumulation of nociceptive substances such as bradykinin, CGRP, and substance P. Elevated cytokines (IL-1β, TNF-α) and fibrosis further increase tissue stiffness and sensitivity.
MTrPs represent a biochemical–mechanical feedback loop in which motor, metabolic, and inflammatory factors interact to sustain pain and contracture. Integrating classical and modern models provides a coherent explanation and supports multimodal physiotherapeutic approaches targeting both muscle function and its biochemical environment.
- OPEN ACCESS ARTICLE - PUBLISHED 2025
BIOCHEMICAL MECHANISMS IN THE FORMATION OF MYOFASCIAL TRIGGER POINTS: AN INTEGRATIVE REVIEW OF RECENT THEORETICAL AND MOLECULAR EVIDENCE
Author:
Tobias Giesen | MSc SEM (UK), BSc PT (NL) Independent Researcher in Physiotherapy and Sports Medicine Germany
Abstract:
Background: Myofascial trigger points (MTrPs) are hyperirritable loci within taut bands of skeletal muscle fibers that elicit local and referred pain upon stimulation. While their clinical relevance is well established, the biochemical and molecular mechanisms underlying their formation remain incompletely explained. Traditional models such as the Energy Crisis Hypothesis proposed ischemia-induced metabolic dysfunction as the initiating factor. Recent research, however, indicates that MTrPs result from a complex interaction between neuromuscular, biochemical, and structural processes, including disturbances in acetylcholine (ACh) regulation, calcium homeostasis, and inflammatory signaling.
Methods: An integrative narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar databases, covering literature from 2015-2025. Foundational pre-2015 studies were included for conceptual continuity. Inclusion criteria comprised peer-reviewed experimental, molecular, and theoretical studies investigating biochemical, neurophysiological, or metabolic aspects of MTrPs. Data extraction focused on five mechanistic domains: motor endplate dysfunction, ion channel regulation, metabolic/ischemic stress, inflammatory mediators, and structural muscle alterations. Quality assessment followed the Joanna Briggs Institute and PRISMA-ScR frameworks.
Results: Five interdependent biochemical domains were identified. Motor endplate hyperactivity—characterized by spontaneous electrical activity and excessive ACh release—was consistently linked to sustained sarcomere contraction and hypoxia. Ion channel dysfunction, particularly in ryanodine receptor (RyR) and K-ATP channels, appeared to maintain intracellular Ca[2] + overload and energy imbalance. Metabolic analyses revealed acidosis, ATP depletion, and accumulation of algogenic mediators such as bradykinin, substance P, serotonin, and CGRP. Elevated cytokines (IL-16, TNF-a) and fibrogenic mediators (TGF-6) contributed to inflammation and structural remodeling, resulting in increased muscle stiffness and decreased elasticity (Zhai et al., 2024).
Discussion: The integrated biochemical model depicts MTrPs as self-sustaining microenvironments where neuromuscular hyperactivity, ionic imbalance, and metabolic exhaustion reinforce one another. The evidence supports Gerwin’s (2023) feedback-control failure theory, complementing the classical Energy Crisis Hypothesis (Simons, 1996). This feedback loop perpetuates both local and central sensitization, explaining the persistence and spread of myofascial pain. While empirical biochemical data remain limited, convergent findings across electrophysiological and imaging studies validate the presence of localized metabolic dysfunction and altered muscle stiffness.
Conclusion: MTrPs represent a multifactorial neuromuscular disorder characterized by disturbed endplate control, calcium dysregulation, ischemia, and inflammation. These mechanisms operate within a closed biochemical-mechanical loop that sustains pain and contracture. Understanding these molecular pathways provides a scientific basis for multimodal physiotherapeutic interventions that target both mechanical and biochemical processes. Future research should standardize diagnostic criteria and employ molecular imaging and microdialysis to clarify causal relationships in MTrP formation.
Keywords:
Myofascial trigger points; biochemistry; acetylcholine; ion channels; calcium regulation; ischemia; inflammation; cytokines; neuromuscular junction; chronic pain; muscle physiology; energy crisis hypothesis
This paper is an independent academic publication in the field of Physiotherapy Science and Sports Medicine. The author declares no institutional affiliation and no conflicts of interest.
1. Introduction
Anterior Myofascial trigger points (MTrPs) represent one of the most persistently debated and clinically significant phenomena in contemporary musculoskeletal pain science. Defined as hyperirritable loci within a taut band of skeletal muscle fibers, they can elicit local and referred pain when mechanically stimulated (Travell & Simons, 1983). Their clinical relevance spans a wide array of pain syndromes—chronic neck pain, tension-type headaches, temporomandibular dysfunction, and low back pain—where they are frequently identified as peripheral generators of nociceptive input (Dommerholt & Huijbregts, 2011; Gerwin, 2023). Despite this ubiquity, the fundamental pathophysiology of MTrPs remains incompletely understood. Most researchers agree that the phenomenon reflects a complex interplay between biomechanical strain, neuromuscular dysregulation, and biochemical alterations within skeletal muscle tissue (Bron et al., 2012).
Historical and conceptual context
The modern concept of MTrPs emerged from the pioneering work of Janet Travell and David Simons, who proposed that discrete foci of abnormal muscle contraction could generate regional pain through localized biochemical and neuromotor abnormalities (Travell & Simons, 1983). Subsequent investigations throughout the late twentieth century framed MTrPs as a distinct peripheral pain generator, giving rise to the energy crisis hypothesis (Simons, 1996). According to this model, sustained sarcomere contraction and local ischemia impair oxidative metabolism, leading to adenosine triphosphate (ATP) depletion, tissue hypoxia, and accumulation of pro-nociceptive metabolites. These include bradykinin, serotonin, calcitonin gene-related peptide (CGRP), prostaglandins, and substance P—all of which sensitize group III and IV afferents, ultimately reinforcing the muscle’s contractile state in a self-perpetuating loop (Shah et al., 2008).
Evolution of pathophysiological models
While the energy crisis hypothesis remains influential, it is increasingly recognized as an oversimplification. Recent evidence suggests that the development of MTrPs cannot be explained solely by peripheral ischemia and metabolic stress. Instead, contemporary models emphasize the involvement of motor endplate dysfunction, ion channel dysregulation, and aberrant neurochemical feedback mechanisms at both pre- and postsynaptic levels (Gerwin, 2023). In this revised framework, disturbances in acetylcholine (ACh) turnover and calcium homeostasis at the neuromuscular junction play pivotal roles. Hyperactivity of the motor endplate leads to sustained sarcomere shortening— observed as “contraction knots”—and may result from either excessive presynaptic ACh release or impaired postsynaptic reuptake. The resulting mechanical compression reduces microvascular perfusion, reinforcing the hypoxic milieu and further disrupting metabolic balance (Gerwin, 2023; Bron et al., 2012).
Ion channelopathies, particularly in the ryanodine receptor (RyR) and K-ATP channels, are proposed to alter the muscle’s ability to regulate intracellular calcium levels and energy expenditure. Dysfunctional RyR signaling can cause continuous calcium leakage from the sarcoplasmic reticulum, sustaining excitation-contraction coupling, while reduced K-ATP responsiveness limits the cell’s capacity to sense ATP depletion and relax appropriately (Gerwin, 2023). These cellular derangements mirror findings in other conditions of muscular hyperexcitability and may explain the spontaneous electrical activity (SEA) consistently recorded in active MTrPs (Liu et al., 2017).
Structural and biochemical milieu
Beyond the neuromuscular junction, imaging and biochemical analyses suggest that MTrPs are characterized by distinct tissue stiffness and compositional heterogeneity. Elastographic studies show that affected regions exhibit increased mechanical stiffness and reduced elasticity compared with nonpainful control sites, possibly reflecting fibrotic remodeling or chronic low-grade ischemia (Zhai et al., 2024). Microdialysis studies—though largely preceding 2015—demonstrated decreased local pH, elevated levels of inflammatory cytokines (IL-1P, TNF-a), catecholamines, and neuropeptides in MTrP tissue (Shah et al., 2008). These data, together with newer molecular theories, indicate that local metabolic stress and altered neuromuscular signaling form an interdependent pathogenic loop.
Integrative and multidimensional understanding
The convergence of mechanical overload, motor endplate hyperactivity, ionic imbalance, and biochemical sensitization positions MTrPs as dynamic neuromyofascial microenvironments rather than static lesions. This perspective integrates peripheral biochemical disturbances with central sensitization phenomena, as persistent nociceptive inflow from MTrPs can induce spinal and supraspinal plasticity, amplifying pain perception and perpetuating the trigger point network (Dommerholt, 2020). The clinical variability of MTrPs—ranging from latent to active, and from localized to widespread—supports a model in which molecular, mechanical, and neurophysiological mechanisms coexist along a continuum rather than representing discrete stages.
Aim of the present work
Given this evolving understanding, the present paper aims to examine the biochemical and molecular foundations of myofascial trigger point formation through a synthesis of recent empirical findings and theoretical advances. Particular emphasis is placed on (1) metabolic stress and ischemic-hypoxic conditions, (2) neurotransmitter and ion channel dysregulation at the motor endplate, and (3) the role of inflammatory mediators and altered extracellular milieu. By critically reviewing and integrating available data, this study seeks to clarify the underlying biochemical framework of MTrPs and outline implications for physiotherapeutic management and future research directions.
2. Methods
This review adopts a narrative integrative design aimed at synthesizing current biochemical, molecular, and electrophysiological evidence regarding the formation of myofascial trigger points (MTrPs). Given the scarcity of high-quality biochemical studies and the diversity of available methodologies, a flexible and conceptually driven approach was preferred over a formal metaanalysis. The integrative framework allows the inclusion of empirical data, theoretical models, and imaging evidence to construct a cohesive explanation of MTrP pathogenesis.
The review draws on both deductive and inductive reasoning: deductive in its reliance on foundational models such as the Energy Crisis Hypothesis (Simons, 1996), and inductive in its synthesis of newer data linking biochemical and neuromuscular dysfunction. The goal was to identify converging mechanisms from multiple research domains—molecular biology, electrophysiology, muscle physiology, and neurochemistry—within a unified conceptual model.
The literature search was performed between January 2020 and October 2025 across major databases including PubMed, Scopus, Web of Science, and Google Scholar. Seminal pre-2020 studies were also reviewed when essential for theoretical continuity, particularly those by Simons (1996), Shah et al. (2008), and Bron et al. (2012). The following Boolean string guided the search:
(“myofascial trigger point” OR “MTrP”) AND (“biochemical” OR “molecular” OR “neurophysiological”) AND (“acetylcholine” OR “ion channel” OR “calcium” OR “ischemia” OR “hypoxia” OR “energy crisis” OR “cytokine” OR “oxidative stress”)
Manual screening of reference lists from key reviews (Gerwin, 2023; Zhai et al., 2024) was performed to identify additional relevant sources. Titles and abstracts were screened for relevance, followed by full-text assessment to ensure methodological suitability. Only peer-reviewed publications were included.
Articles were included if they addressed biochemical or molecular aspects of MTrPs or related muscle pain syndromes, were published in English between 2015 and 2025, and applied recognized diagnostic criteria for trigger points. Both empirical and theoretical works were accepted when grounded in physiological evidence. Exclusion criteria eliminated non-peer-reviewed materials, purely therapeutic trials without mechanistic data, and unrelated pain syndromes unless direct parallels were drawn to MTrP pathophysiology.
Data extraction followed a structured template based on PRISMA-ScR and Joanna Briggs Institute guidelines. For each study, information was collected on publication details, study design, methodology (e.g., microdialysis, electromyography, elastography), key biochemical variables (such as pH, acetylcholine, calcium flux, cytokine levels, and ion channel function), and principal findings. The extracted data were then grouped into five major thematic domains: motor endplate dysfunction, ion channel dysregulation, metabolic and ischemic stress, inflammatory and neurochemical milieu, and structural muscle changes.
Rather than quantitative pooling, findings were synthesized qualitatively through thematic analysis. Recurring biochemical and physiological mechanisms were identified, compared, and integrated to determine convergence between independent lines of evidence. Contradictory findings were examined critically with attention to methodological rigor and the plausibility of results within established muscle physiology.
Quality assessment was performed using the Joanna Briggs Institute critical appraisal tools for experimental and observational studies, and the AMSTAR-2 checklist for reviews (Shea et al., 2017). Studies were judged on the clarity of MTrP identification, control of confounding factors, reproducibility of assays, and reporting transparency. The inclusion of theoretical articles, such as Gerwin’s (2023) model of feedback failure at the neuromuscular junction, was justified by their mechanistic significance and coherence with existing biochemical data.
The final synthesis integrated results from molecular, electrophysiological, and imaging studies into an evolving model of MTrP formation. The process unfolded in three stages: descriptive mapping of all included works, identification of recurring biochemical themes, and construction of an integrative pathophysiological framework. This model links peripheral biochemical changes—such as acetylcholine overrelease, calcium dysregulation, and ischemic acidification—to broader neuromuscular dysfunction and pain sensitization.
Although this review followed recognized methodological frameworks, several limitations are acknowledged. The heterogeneity of diagnostic criteria for MTrPs and the predominance of crosssectional designs restrict causal inference. Direct biochemical evidence remains limited, as most studies rely on surrogate measures like tissue stiffness or spontaneous electrical activity rather than direct molecular sampling. Despite these challenges, integrating diverse evidence types provides valuable insight into the biochemical foundations of trigger point formation and maintenance.
3. Results
The analysis of the included studies revealed five major mechanistic domains underlying the formation and persistence of myofascial trigger points (MTrPs): motor endplate dysfunction, ion channel dysregulation, metabolic and ischemic stress, inflammatory and neurochemical milieu alterations, and structural and viscoelastic muscle changes. Together, these mechanisms form a multilayered model that integrates biochemical and neurophysiological evidence into a coherent pathophysiological framework.
The first and most consistently supported finding across studies concerns motor endplate dysfunction. Gerwin (2023) and Liu et al. (2017) demonstrated that active MTrPs exhibit abnormal spontaneous electrical activity (SEA), suggesting persistent depolarization of the neuromuscular junction. This hyperactivity appears to be linked to excessive presynaptic acetylcholine (ACh) release and failure of local inhibitory feedback loops. The hypersecretion of ACh leads to continuous calcium influx into muscle fibers, maintaining partial contraction of sarcomeres—observed histologically as “contraction knots.” As a result, local perfusion becomes compromised, creating a hypoxic environment that perpetuates metabolic distress. Although the exact biochemical trigger for endplate hyperexcitability remains uncertain, evidence points to the malfunction of pre- and postsynaptic modulators that normally regulate ACh turnover (Gerwin, 2023; Dommerholt, 2020).
Closely related to motor endplate changes is ion channel dysregulation, particularly involving the ryanodine receptor (RyR) and ATP-sensitive potassium (K-ATP) channels. Gerwin (2023) proposed that defective RyR signaling allows continuous leakage of Ca[2]+ from the sarcoplasmic reticulum, preventing muscle relaxation and promoting sustained contraction. In parallel, impaired K-ATP channel function may limit the fiber’s ability to detect and respond to ATP depletion, leading to an energy-inefficient state. These mechanisms explain the observed persistence of taut bands even in the absence of voluntary contraction and align with the metabolic fatigue patterns seen in electromyographic analyses. While direct evidence for ion channel mutations in MTrPs is still lacking, the biochemical plausibility of such dysfunction is reinforced by parallels to other muscle hyperexcitability disorders.
The domain of metabolic and ischemic stress represents a cornerstone of MTrP biochemistry. Early work by Shah et al. (2008) demonstrated significantly reduced pH and increased levels of inflammatory and nociceptive substances (including bradykinin, CGRP, serotonin, and norepinephrine) in active MTrPs compared with control muscle tissue. These findings are supported conceptually by the Energy Crisis Hypothesis (Simons, 1996), which links sustained contraction to impaired microcirculation, ATP depletion, and accumulation of metabolic by-products. Recent imaging data using shear-wave elastography suggest that these hypoxic regions correspond to zones of increased stiffness and reduced oxygenation (Zhai et al., 2024). Together, these data confirm that biochemical and mechanical dysfunctions coexist in a self-reinforcing loop—ischemia promotes metabolic acidosis, which in turn enhances nociceptor activation and further muscle contraction.
Within the inflammatory and neurochemical milieu, modern studies have emphasized the role of cytokine signaling and neuropeptide release. Although the majority of quantitative biochemical work stems from pre-2015 investigations, the mechanisms remain relevant. Elevated interleukin-1 P (IL-1P) and tumor necrosis factor alpha (TNF-a) have been identified in affected tissue (Shah et al., 2008), and these mediators are known to upregulate peripheral nociceptor sensitivity through TRPV1 receptor modulation. Furthermore, the local increase of CGRP and substance P enhances neurogenic inflammation, altering microvascular tone and perpetuating the hypoxic microenvironment. Gerwin’s (2023) unified theory integrates these mediators into a broader network of feedback failure, where sympathetic overactivity amplifies both vascular constriction and neurotransmitter release at the motor endplate.
A fifth recurring pattern involves structural and viscoelastic changes in the muscle matrix surrounding MTrPs. Recent elastography and ultrasound investigations (Zhai et al., 2024) demonstrated that MTrPs exhibit greater stiffness, lower elasticity, and deeper localization within muscle fibers compared with non-painful control regions. These findings imply chronic alterations in extracellular matrix composition, including potential fibrosis and collagen cross-linking due to recurrent ischemia and oxidative stress. Such structural adaptations may impede nutrient diffusion and delay metabolite clearance, thereby maintaining the biochemical environment that sustains trigger point activity.
When viewed collectively, these domains form an integrative model of MTrP formation. Mechanical overuse or repetitive strain initiates localized motor endplate hyperactivity, driven by excessive ACh release. This activity induces sarcomere contraction and capillary compression, resulting in regional hypoxia and impaired ATP regeneration. Ion channel dysfunction—particularly in RyR and K-ATP pathways—further inhibits recovery, while accumulated metabolites and inflammatory mediators sensitize nociceptors. Over time, structural remodeling and fibrosis reinforce the contractile state, converting an initially reversible dysfunction into a chronic pain generator.
Although the strength of evidence varies between domains, there is a consistent convergence across biochemical, electrophysiological, and imaging studies. The most robust empirical support exists for local acidosis, spontaneous endplate activity, and tissue stiffness. Ion channel alterations remain theoretical but increasingly plausible given their coherence with muscle physiology. The interaction of these factors highlights MTrPs as complex microenvironments where mechanical, metabolic, and neurochemical feedback loops become pathologically interlocked.
4. Discussion
The synthesis of current evidence highlights that the biochemical landscape of myofascial trigger points (MTrPs) is neither a simple by-product of mechanical overload nor an isolated local lesion. Instead, MTrPs emerge from an interdependent network of neuromuscular, metabolic, and inflammatory processes that collectively distort normal muscle homeostasis. This integrated model supports the view that the perpetuation of trigger points reflects a breakdown of several protective physiological systems—most notably the regulation of acetylcholine (ACh) at the motor endplate, intracellular calcium homeostasis, and microvascular perfusion.
At the molecular level, the strongest body of evidence continues to implicate motor endplate dysfunction as a primary driver of MTrP initiation. Persistent spontaneous electrical activity (SEA) recorded from active MTrPs (Liu et al., 2017) is consistent with continuous, involuntary depolarization of muscle fibers. This phenomenon has been directly associated with increased ACh release from presynaptic terminals (Gerwin, 2023) and failure of local inhibitory feedback via muscarinic autoreceptors. The result is excessive excitation-contraction coupling, with intracellular Ca[2]+ accumulation maintaining sarcomere shortening even in the absence of voluntary activation. Such sustained contraction creates mechanical compression of capillaries, leading to tissue ischemia and the cascade of metabolic disturbances described in Simons’s Energy Crisis Hypothesis (Simons, 1996).
However, newer models refine this view by incorporating ion channel dysregulation as a key biochemical amplifier. The proposed dysfunction of ryanodine receptors (RyR) and K-ATP channels (Gerwin, 2023) bridges the gap between metabolic depletion and sustained electrical activity. Abnormal RyR signaling permits continuous calcium leakage from the sarcoplasmic reticulum, preventing repolarization, while impaired K-ATP channel function inhibits the muscle fiber’s protective relaxation response to ATP depletion. The biochemical plausibility of these mechanisms aligns with broader muscle physiology research, where similar ion-handling anomalies are known to underlie malignant hyperthermia and certain myopathies. Though direct molecular confirmation in human MTrPs remains limited, this theoretical extension provides a coherent explanation for the persistence and recurrence of trigger point activity even after mechanical load is removed.
Within the hypoxic and metabolically compromised environment of an MTrP, accumulation of inflammatory and neuroactive mediators further reinforces the pain and dysfunction cycle. Microdialysis data from Shah et al. (2008) demonstrated elevated concentrations of bradykinin, CGRP, substance P, serotonin, and cytokines such as interleukin-1 P (IL-1P) and tumor necrosis factor alpha (TNF-a) within active trigger points. These mediators collectively lower local pH, sensitize nociceptors, and increase vascular permeability. In turn, the resultant edema exacerbates local hypoxia and perpetuates nociceptive input. The role of CGRP and substance P is particularly important, as these neuropeptides modulate ACh release at the motor endplate and thus link biochemical inflammation directly to neuromuscular hyperactivity (Bron et al., 2012; Dommerholt, 2020).
This interaction of biochemical and neural factors underscores the bidirectional relationship between peripheral and central sensitization. Persistent nociceptive input from hyperactive MTrPs may induce spinal sensitization, reducing inhibitory interneuron activity and enhancing dorsal horn excitability. Central sensitization, in turn, lowers the activation threshold of peripheral nociceptors, creating a feedback loop that maintains trigger point sensitivity. Functional neuroimaging studies in chronic myofascial pain (Dommerholt, 2020) support this model, revealing increased activity in painprocessing regions of the brainstem and sensorimotor cortex in response to peripheral stimulation of trigger points.
Structural evidence further supports a chronic remodeling of the muscle microenvironment. Zhai et al. (2024) showed, through ultrasound elastography, that active MTrPs display higher stiffness, lower elasticity, and deeper localization than latent or control sites. These findings suggest the presence of fibrosis, altered extracellular matrix composition, and chronic ischemia. From a biochemical standpoint, these structural changes may be mediated by reactive oxygen species (ROS) and fibrogenic cytokines such as transforming growth factor beta (TGF-P), which are upregulated under sustained hypoxic stress. The result is a maladaptive cycle of decreased perfusion, increased collagen deposition, and continued contracture—transforming what may begin as a reversible metabolic lesion into a persistent pathophysiological state.
Taken together, these data support a multifactorial pathogenesis model in which mechanical, biochemical, and neural components interact dynamically. Initial microtrauma or repetitive strain provokes endplate hyperactivity and metabolic imbalance; biochemical mediators such as cytokines and neuropeptides amplify pain signaling; ion channel dysfunction sustains calcium overload; and chronic inflammation reshapes tissue structure. The combined effect is a self-perpetuating “closed biochemical loop,” where impaired energy metabolism, ionic imbalance, and nociceptive activation continuously reinforce one another.
Despite the conceptual coherence of this model, several limitations in the current body of evidence must be acknowledged. First, quantitative biochemical data remain scarce. Most studies rely on microdialysis of a limited number of subjects, with small sample sizes and variable diagnostic criteria. Replication is rare, and inter-laboratory standardization is lacking. Second, much of the molecular evidence for ion channel dysfunction is inferred rather than directly observed. While plausible, it depends on extrapolation from other muscle pathologies. Third, many studies are cross-sectional, precluding determination of temporal causality—whether biochemical disturbances precede trigger point formation or result from chronic pain remains uncertain.
Another major challenge is the lack of standardized diagnostic definitions. Quintner et al. (2015) criticized the variability and subjectivity in MTrP identification, warning that inconsistent criteria undermine reproducibility and external validity. Until diagnostic procedures are unified—possibly through integration of elastographic imaging, EMG mapping, and biochemical profiling—mechanistic research will continue to face methodological constraints.
Nonetheless, the convergence of independent evidence streams—electrophysiological, imagingbased, and biochemical—supports the interpretation that MTrPs represent a localized biochemical and neuromuscular dysfunction rather than an epiphenomenon. The integration of Gerwin’s (2023) feedback-control failure model with the Energy Crisis and inflammatory hypotheses offers the most comprehensive framework currently available. This synthesis advances the field beyond purely mechanical explanations and provides a biologically plausible rationale for the persistence, recurrence, and widespread referral patterns characteristic of myofascial pain.
Clinically, these findings emphasize the need for multimodal physiotherapeutic strategies that target not only mechanical dysfunction but also the biochemical environment of affected muscle tissue. Interventions that improve local perfusion, modulate endplate excitability, and address systemic inflammatory states—such as graded exercise, manual therapy, dry needling, and possibly nutritional or pharmacological modulation of muscle metabolism—may be most effective when applied within an integrated treatment framework.
Ultimately, while many mechanistic pathways remain hypothetical, the biochemical model of MTrPs has shifted from peripheral speculation to a physiologically grounded, system-level explanation of chronic myofascial pain. Continued interdisciplinary research combining molecular biology, neurophysiology, and biomechanics is essential to validate and refine this evolving paradigm.
5. Conclusion
Current evidence indicates that myofascial trigger points (MTrPs) are not isolated mechanical lesions but reflect a multifactorial biochemical and neuromuscular dysfunction. They represent localized zones of disrupted muscle homeostasis in which excessive acetylcholine (ACh) release, disturbed calcium regulation, metabolic exhaustion, and inflammatory signaling interact to produce sustained contraction, ischemia, and pain.
Central to this process is motor endplate hyperactivity, supported by the presence of spontaneous electrical activity (Liu et al., 2017) and Gerwin’s (2023) model of feedback failure at the neuromuscular junction. Persistent ACh release leads to calcium overload, impaired ATP regeneration, and a hypoxic microenvironment rich in algogenic mediators such as bradykinin, substance P, serotonin, and CGRP (Shah et al., 2008). These biochemical changes activate nociceptors and reinforce muscle tension, creating a self-perpetuating feedback loop.
Additional mechanisms—particularly ion channel dysfunction (ryanodine receptor, K-ATP channels) and inflammatory remodeling—help explain the chronicity of MTrPs. Cytokines such as IL-ip and TNF-a, along with fibrogenic factors like TGF-p, promote tissue stiffness and microvascular compromise (Zhai et al., 2024). This biochemical-mechanical coupling contributes to the persistence of taut bands and pain sensitivity even after the initial injury subsides.
Clinically, these findings justify multimodal physiotherapeutic approaches that address both mechanical and biochemical dimensions—improving local perfusion, reducing endplate excitability, and modulating inflammation. Yet substantial research gaps remain: biochemical data are scarce, diagnostic criteria are inconsistent, and causality is unresolved.
In summary, MTrPs appear to result from an integrated cycle of endplate overactivity, ionic imbalance, metabolic stress, and inflammatory change. This “closed biochemical loop” provides a coherent explanation for their chronic nature and suggests that future research must combine molecular, electrophysiological, and imaging techniques to clarify their true pathophysiology.
Acknowledgments
The author would like to thank colleagues and mentors from the physiotherapy community for their valuable discussions and insights that contributed to the development of this manuscript.
Conflict of Interest Statement
The author declares no conflicts of interest related to this work.
He is an independent physiotherapist and researcher and received no financial or material support for this study.
Funding Statement
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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- Tobias Giesen (Autor), 2025, Biochemical Mechanisms in the Formation of Myofascial Trigger Points. An Integrative Review of Recent Theoretical and Molecular Evidence, Múnich, GRIN Verlag, https://www.grin.com/document/1670893
