Rethinking the Biology of Skeletal Muscle Hypertrophy: Beyond mTOR and Acute Muscle Protein Synthesis
Subject Areas : Sport Physiology
Shahin Riyahi Malayeri
1
,
Reza Rostami
2
*
,
Mahmoud ZohrabZadeh
3
1 - Department of Physical Education and Sport Sciences, ET.C., Islamic Azad University, Tehran, Iran.
2 - Department of Physical Education and Sport Sciences, ET.C., Islamic Azad University, Tehran, Iran.
3 - Department of Exercise Physiology, CT.C., Islamic Azad University, Tehran, Iran.
Keywords: Muscle Hypertrophy, Skeletal Muscle, Protein Synthesis,
Abstract :
Dear Editor,
Skeletal muscle hypertrophy remains one of the most extensively investigated adaptations to resistance training (RT), yet its underlying biology is considerably more complex than the conventional model of “mechanical loading - mTOR activation - muscle protein synthesis (MPS) - muscle growth” (1,2). Although this framework has been fundamental to the development of contemporary exercise physiology, recent evidence indicates that hypertrophy is better understood as an emergent phenotype arising from the interaction of mechanical, molecular, cellular, nutritional, and individual factors (2,13,15). We suggest that the current discussion should move beyond the isolated interpretation of acute anabolic signaling and instead consider the integration of mechanotransduction, translational capacity, protein turnover, satellite-cell activity, and individual responsiveness (2,13,15). Mechanical tension remains the most defensible proximal stimulus for resistance-training-induced hypertrophy (1,2,10). However, the biological interpretation of mechanical tension has evolved. Mechanical loading is detected through multiple structures within the muscle fiber and its extracellular environment, including the sarcolemma, cytoskeleton, costameric complexes, integrin-associated structures, and the extracellular matrix. These systems convert mechanical deformation into intracellular signals that regulate transcription, translation, cytoskeletal remodeling, and cellular growth (2,10,15). Accordingly, the external characteristics of a resistance exercise—load, repetitions, range of motion, contraction type, and proximity to failure—should not be regarded as direct determinants of hypertrophy. Rather, they modify the internal mechanical and metabolic environment that ultimately governs adaptation (1,6,10,18). This distinction has important implications for the interpretation of mTORC1 signaling. Activation of mTORC1 and its downstream effectors, including p70S6 kinase and 4E-BP1, is clearly involved in the regulation of translational activity following resistance exercise (2,13). Nevertheless, transient increases in phosphorylation of anabolic signaling proteins should not be equated with long-term muscle growth (2,13,15). The hypertrophic phenotype develops through repeated exposure to mechanical stimuli and the cumulative remodeling of muscle tissue. Consequently, molecular signaling should be interpreted as part of a network rather than as a single molecular switch responsible for hypertrophy (2,13,15). A similar caution is warranted regarding MPS. Resistance exercise increases MPS during recovery, and amino acid availability can further augment this response (4,11,13). However, the relationship between an acute post-exercise increase in MPS and subsequent hypertrophy is not necessarily linear. The timing, magnitude, duration, and protein fraction measured are critical (2,13). Myofibrillar protein synthesis is more directly related to contractile tissue remodeling than total MPS, while mitochondrial, sarcoplasmic, and extracellular matrix proteins may exhibit distinct temporal responses (13,17). Furthermore, the acute MPS response can be influenced by training status and does not necessarily predict the magnitude of hypertrophy over subsequent weeks or months (2,13).
This issue suggests that the field should increasingly distinguish between anabolic signaling, acute protein synthesis, and net protein accretion. Muscle hypertrophy ultimately reflects the cumulative balance between protein synthesis and protein degradation, integrated across repeated training and recovery cycles (13,17). A transient increase in MPS is therefore necessary in many circumstances but is not, by itself, sufficient evidence that a specific intervention will produce superior hypertrophy. Recent conceptual and experimental work has emphasized that resistance exercise affects both synthetic and degradative processes and that their temporal coordination may be more informative than isolated measurements of MPS (13,17). Another relatively underappreciated determinant is ribosomal biogenesis. Muscle growth requires not only activation of existing translational machinery but also sufficient translational capacity to sustain increased protein production over time. Repeated resistance exercise can increase ribosomal content and alter the molecular systems controlling ribosomal RNA synthesis. This provides a plausible mechanistic bridge between repeated acute anabolic responses and chronic hypertrophy (2,13,17). In this context, training volume may influence hypertrophy partly by modifying the translational capacity of skeletal muscle rather than merely by increasing the number of mechanical stimuli (17,19).
Satellite cells provide a further layer of biological regulation. These muscle-resident progenitor cells respond to mechanical loading and participate in muscle remodeling, regeneration, and, under some circumstances, myonuclear accretion. Importantly, the contemporary literature does not support a simplistic interpretation in which satellite cells are either universally essential or completely irrelevant to hypertrophy (2,15). Their contribution appears to depend on training history, exercise characteristics, muscle group, magnitude of the hypertrophic stimulus, and the physiological context. Recent evidence showing differences in satellite-cell responses among individuals with different hypertrophic trajectories reinforces the concept that cellular remodeling may contribute to interindividual variability (2,15). The concept of individual responsiveness may therefore deserve greater prominence in hypertrophy research. Identical resistance-training programs do not produce identical morphological adaptations (1,18). Recent investigations have demonstrated that individuals can respond differently to alternative overload progression strategies, with some participants exhibiting substantially greater hypertrophy under one progression model than another. Such findings challenge the assumption that a universal resistance-training prescription can optimize hypertrophy across all individuals (18,19). Instead, the field may need to move toward adaptive training models in which training volume, loading strategy, proximity to failure, exercise selection, and progression are adjusted according to measurable responses. The debate surrounding proximity to failure illustrates this principle. Contemporary evidence suggests that training closer to momentary muscular failure may enhance hypertrophic responses under some conditions, but failure itself is not consistently required (3,6,7). Indeed, recent controlled work has reported similar hypertrophy when resistance-trained individuals performed sets to momentary failure or terminated sets with repetitions in reserve (8). The physiological consequence of failure may therefore depend on the interaction between load, volume, exercise selection, fatigue, and the muscle's capacity to maintain high mechanical tension (3,6,8). Training volume presents a similar complexity. Higher weekly volumes are generally associated with greater hypertrophy, but the relationship is not necessarily unlimited or linear (1,19). The traditional interpretation that “more sets always produce more growth” is increasingly difficult to defend without considering training status, recovery capacity, exercise selection, and the distribution of volume across the week (1,19). Interestingly, recent experimental evidence indicates that even a large increase in training volume does not necessarily impair hypertrophy or anabolic-catabolic molecular signaling in trained individuals (20). This suggests that the biological response to training volume is highly context-dependent.
Nutritional regulation should also be integrated into this model. Dietary protein supplies the amino acids required for tissue remodeling, while essential amino acids—particularly leucine—can influence nutrient-sensing pathways involved in translational regulation (4,11). However, protein intake does not operate independently of mechanical loading. The interaction between resistance exercise and nutrition is more appropriately understood as a coordinated system in which mechanical stimuli establish the requirement for remodeling while amino acid availability supports the substrate and signaling environment necessary for protein accretion (4,11,13). Recent work also indicates that the timing of protein ingestion may be less important than achieving an adequate total daily protein intake in resistance-trained individuals (4,11). Another emerging issue is the distinction between muscle size and muscle quality. Hypertrophy assessed through a single anthropometric measurement or whole-body lean mass may obscure regional and architectural adaptations. Muscle thickness, anatomical cross-sectional area, muscle volume, fascicle length, pennation angle, and tissue composition can change heterogeneously within the same muscle (9,10). Therefore, future hypertrophy studies should increasingly combine morphological, architectural, molecular, and functional outcomes. This multidimensional approach would reduce the risk of interpreting small changes in body composition as direct evidence of contractile tissue hypertrophy (9). The 2026 American College of Sports Medicine overview of reviews further supports a more nuanced interpretation of resistance-training prescription. Across more than 30,000 participants and 137 systematic reviews, resistance training consistently improved muscle size and function, whereas relatively few individual prescription variables demonstrated uniform effects across outcomes (18). Higher weekly volume was associated with greater hypertrophy, but several commonly emphasized variables—including training to momentary fatigue, equipment type, exercise complexity, time under tension, blood-flow restriction, and periodization—did not consistently influence all outcomes (18). These findings emphasize that hypertrophy should be viewed as a biological adaptation emerging from an integrated training stimulus rather than from a single optimal training variable. Collectively, the evidence supports a revised conceptual framework in which mechanical loading initiates mechanotransduction; intracellular signaling involving mTORC1 and related pathways regulates translational activity; repeated stimulation modifies ribosomal capacity; MPS and protein degradation determine the net remodeling environment; satellite cells and myonuclear adaptations contribute to tissue plasticity; and nutritional availability modulates the capacity to sustain these processes (2,13,15,17). The magnitude of the final hypertrophic phenotype is subsequently shaped by training history, recovery, age, sex, nutritional status, and individual responsiveness (1,18,19). We therefore propose that future research should move from the question “Which training variable maximizes MPS?” toward the more physiologically meaningful question “Which combination of mechanical, molecular, cellular, and nutritional signals maximizes sustained contractile protein accretion in a given individual?” Addressing this question will require longitudinal studies integrating repeated measures of MPS, proteolysis, ribosomal biogenesis, satellite-cell behavior, muscle architecture, and functional performance (2,13,17). Such an approach may help explain why apparently similar training programs produce markedly different hypertrophic outcomes.
In conclusion, mTORC1 and MPS remain central components of skeletal muscle hypertrophy, but neither should be regarded as a sufficient explanation of the hypertrophic phenotype (2,13,15). The emerging evidence favors an integrated model in which mechanical tension is translated through multiple intracellular systems and ultimately interacts with translational capacity, protein turnover, cellular remodeling, nutrition, and individual biology (2,13,15,17). Reframing hypertrophy in this manner may improve mechanistic understanding while also providing a stronger scientific foundation for individualized resistance-training prescription (18,19).
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