The Rho GTPase Rac1 mediates exercise training adaptations

Exercise training elicits tremendous health benefits; however, the molecular underpinnings are poorly understood. As one of the most regulated groups of proteins following acute exercise in human muscle, Rho GTPases are unexplored candidates for mediating the beneficial effects of exercise. The Rho GTPase Rac1 was activated during multiple exercise modalities and remained elevated hours after resistance exercise in human muscle. Inducible muscle-specific Rac1 knockout (Rac1 imKO) mice, displayed attenuated muscle protein synthesis, glycogen resynthesis and p38 MAPK signaling in recovery from contractions. Exercise training upregulated Rac1 protein content in human and mouse muscle. Overexpression of hyperactive Rac1 elevated reactive oxidant species production during exercise yet did not induce a trained muscle phenotype. In Rac1 imKO mice, the improvements in running capacity and muscle mass after exercise training were diminished. Using gain- and loss-of-function mouse models and human muscle biopsies, we identify Rac1 as a regulator of exercise training adaptions. Highlights Various exercise modalities activate Rac1 signaling in human skeletal muscle. HSP27, MNK1, and CREB are Rac1-dependent contraction-responsive targets in muscle. Post-contraction protein synthesis requires Rac1 but not NOX2. Rac1-NOX2 signaling is necessary for post-contraction glycogen resynthesis. Exercise training increases Rac1 protein content in human and mouse muscles. Rac1 mediates critical adaptations to exercise training.