Identification of a Resistance Exercise-Specific Signaling Pathway that Drives Skeletal Muscle Growth

A human model of unilateral endurance versus resistance exercise, in conjunction with deep phosphoproteomic analyses, was used to identify exercise mode-specific phosphorylation events. Among the outcomes, a resistance exercise-specific cluster of events was identified, and a multitude of bioinformatic- and literature-based predictions suggested that this was mediated by prolonged activation of a pathway involving MKK3b/6, p38, MK2, and mTORC1. Follow-up studies in humans and mice provide consistent support for the predictions and also revealed that resistance exercise-induced signaling through MKK3b and the induction of protein synthesis are highly correlated events (R = 0.87). Moreover, genetic activation of MKK3b/6 in skeletal muscles was sufficient to induce signaling through the members of the resistance exercise-specific pathway, as well as an increase in protein synthesis and fiber size. Thus, we propose that we have identified some of the core components of a signaling pathway that drives the growth-promoting effects of resistance exercise.