In the relentless pursuit of physical fitness, the distinction between endurance and resistance exercise has long been recognized, yet the molecular mechanisms orchestrating their unique adaptations have remained elusive. Endurance exercise is celebrated for its capacity to enhance aerobic performance, augmenting mitochondrial biogenesis and oxidative metabolism. In stark contrast, resistance exercise is the cornerstone of muscle hypertrophy, promoting increased muscle mass and strength. The divergent physiological outcomes provoke a fundamental question: what cellular signalling pathways selectively govern these adaptations?
Recent pioneering work has illuminated a novel, resistance-exercise-specific signalling cascade that underpins skeletal muscle growth. A study led by Zhu, Thomas, Wilson, and colleagues, soon to be published in Nature Metabolism, utilized an innovative unilateral exercise model in human participants combined with comprehensive phosphoproteomic analyses to disentangle the intricate web of signalling events triggered by different exercise modalities. Their findings unveil a sustained activation of a pathway involving MKK3b/6, p38 MAP kinase, MK2, and the mechanistic target of rapamycin complex 1 (mTORC1), exclusively in response to resistance exercise stimuli.
Phosphorylation, the reversible addition of phosphate groups to proteins, serves as a critical switch modulating protein function and signalling dynamics. By employing deep phosphoproteomics, the researchers mapped the phosphorylation landscape post-exercise, identifying unique signatures that discriminate between endurance and resistance exercise responses. In resistance-exercised muscles, phosphorylation of MKK3b and its downstream effectors p38 and MK2 was markedly elevated and prolonged, setting the stage for potent anabolic signalling.
The role of mTORC1 as a central anabolic hub is well-established across various growth stimuli. Interestingly, this study positions MKK3b-p38-MK2 signalling upstream of mTORC1 activation specifically in the context of resistance exercise. This hierarchical arrangement suggests a novel mechanism of mTORC1 regulation that integrates extracellular mechanical cues into the biochemical framework driving protein synthesis and hypertrophy.
Subsequent human trials incorporating both male and female participants cemented the physiological relevance of this pathway. By correlating phosphorylation levels of MKK3b with markers of protein synthesis, the team demonstrated a striking positive correlation (R = 0.87), underscoring MKK3b’s pivotal role as a molecular switch orchestrating growth responses. This strong association not only validates the pathway’s involvement but also potentially positions MKK3b as a biomarker for hypertrophic adaptation.
The translational potential of these findings was further affirmed in preclinical mouse models. Genetic activation of MKK3b recapitulated the signalling cascade observed in humans, provoking robust activation of p38, MK2, and mTORC1. Notably, this molecular activation was accompanied by measurable increases in protein synthesis rates and muscle fiber size, confirming the functional consequences of engaging this pathway at the cellular level.
This discovery challenges the traditional view that mechanical loading alone suffices for hypertrophy, instead highlighting the necessity of precise biochemical signalling via the MKK3b-p38-MK2-mTORC1 axis. Such insights offer fertile ground for therapeutic strategies aimed at ameliorating muscle wasting disorders, sarcopenia, and enhancing recovery in clinical settings.
From a mechanistic standpoint, MKK3b (a MAP kinase kinase) functions as a critical intermediary, phosphorylating and activating p38 MAP kinase, which in turn recruits and phosphorylates MK2. MK2 has been implicated in regulating various downstream effectors, including those influencing translation machinery and cytoskeletal remodeling. The engagement of mTORC1 downstream integrates anabolic signalling, promoting ribosomal biogenesis and elongation during protein synthesis — essential steps in muscle hypertrophy.
Understanding why this pathway remains quiescent during endurance exercise adds a fascinating layer of complexity. Endurance training predominantly activates AMP-activated protein kinase (AMPK) and related pathways, fostering mitochondrial adaptations and fatigue resistance, yet it appears to exclude the activation of the MKK3b axis. This suggests an elegant division of intracellular signalling based on exercise modality, with mechanosensitive and metabolic sensors operating in parallel or mutual exclusivity to fine-tune physiological remodeling.
Beyond fundamental science, the identification of a resistance-exercise-specific signalling pathway bears significant implications for athletic training and rehabilitation protocols. Monitoring phosphorylation states of MKK3b or its downstream effectors could serve as a sensitive indicator of muscle responsiveness and adaptation, guiding personalized exercise prescriptions for optimal hypertrophic outcomes.
Moreover, pharmaceutical modulation of components within this pathway might one day mimic the anabolic effects of resistance exercise, providing therapeutic hope for individuals unable to engage in physical training due to injury or chronic disease. Targeting upstream kinases like MKK3b or modulating the p38-MK2 axis could be harnessed to selectively activate mTORC1 signalling, stimulating muscle growth with precision.
The comprehensive nature of the phosphoproteomic approach in this study also sets a new standard for exercise physiology research. By capturing temporal dynamics and multiple phosphorylation sites, the team unveiled a signalling "fingerprint" unique to resistance training. This multidimensional perspective enriches our understanding of how transient biochemical signals translate into enduring morphological changes.
Critically, the study bridges species by validating human findings in murine models, establishing both physiological and mechanistic causality. This cross-validation enhances confidence in the translational value of the pathway, paving the way for future interventional studies.
The gender-inclusive design of follow-up experiments further ensures broad applicability, recognizing that sex-specific differences in muscle physiology often complicate extrapolation. By confirming pathway activation in both male and female participants, the research affirms a universal mechanism driving hypertrophy across sexes.
While the study centers on phosphorylation-mediated signalling, it inevitably prompts questions regarding upstream regulators—what molecular sensors detect the mechanical strain or metabolic shifts that selectively engage MKK3b in resistance but not endurance exercise? Identifying such mechanosensors or co-factors represents an exciting frontier for subsequent inquiry.
In conclusion, the elucidation of the MKK3b-p38-MK2-mTORC1 signalling axis as a dedicated conduit for muscle growth induced by resistance exercise represents a milestone in exercise biology. It delineates a precise biochemical pathway transforming mechanical stimuli into molecular commands that build muscle mass, compelling a reevaluation of how we conceptualize exercise adaptation at the cellular level. As this knowledge permeates into clinical and athletic arenas, it promises to revolutionize both therapeutic muscle regeneration and performance optimization strategies in the years ahead.
Subject of Research: Signalling pathways governing skeletal muscle adaptation to resistance exercise
Article Title: Identification of a resistance-exercise-specific signalling pathway that drives skeletal muscle growth
Article References:
Zhu, W.G., Thomas, A.C.Q., Wilson, G.M. et al. Identification of a resistance-exercise-specific signalling pathway that drives skeletal muscle growth.
Nat Metab (2025). https://doi.org/10.1038/s42255-025-01298-7
Image Credits: AI Generated
