Identification of a resistance-exercise-specific signalling pathway that drives skeletal muscle growth

Endurance and resistance exercise lead to distinct functional adaptations: the former increases aerobic capacity and the latter increases muscle mass. However, the signalling pathways that drive these adaptations are not well understood. Here we identify phosphorylation events that are differentially regulated by endurance and resistance exercise. Using a model of unilateral exercise in male participants and deep phosphoproteomic analyses, we find that a prolonged activation of a signalling pathway involving MKK3b/6, p38, MK2 and mTORC1 occurs specifically in response to resistance exercise. Follow-up studies in both male and female participants reveal that the resistance-exercise-induced activation of MKK3b is highly correlated with the induction of protein synthesis (R = 0.87). Additionally, we show that in mice, genetic activation of MKK3b is sufficient to induce signalling through p38, MK2 and mTORC1, along with an increase in protein synthesis and muscle fibre size. Overall, we identify core components of a signalling pathway that drives the growth-promoting effects of resistance exercise.