Putting the brakes on muscle growth: Myostatin as regulator of disuse atrophy

Skeletal muscle is a highly plastic tissue that rapidly adapts to changes in mechanical loading and metabolic activity. Periods of inactivity, including bed rest, limb immobilization or microgravity, induce a pronounced loss of muscle mass and function. This review examines the mechanistic role of myostatin (growth differentiation factor-8; GDF-8), a member of the transforming growth factor-β superfamily, in mediating inactivity-induced skeletal muscle atrophy. Accumulating evidence from human and rodent studies demonstrates that physical inactivity upregulates myostatin expression and signalling, shifting muscle protein turnover toward net protein degradation. Mechanistically, myostatin binds to the activin type IIB receptor (ActRIIB) and activates Smad2/3 signalling, which suppresses Akt phosphorylation and downstream mTOR activity, resulting in reduced protein translation. Diminished Akt signalling activates FoxO transcription factors, promoting ubiquitin-proteasome-mediated proteolysis. In parallel, myostatin maintains satellite cells in a quiescent state, impairing MyoD-driven activation and limiting myogenesis, thereby reducing regenerative capacity during and after physical inactivity. We provide a narrative mini-review on the time course of gene expression of myostatin during inactivity. Finally, these mechanistic insights have stimulated therapeutic strategies targeting the myostatin-ActRIIB axis, notably bimagrumab, a monoclonal antibody against ActRIIB and inhibitor of downstream myostatin signalling. Evidence from human and rodent studies suggests that myostatin inhibition may represent a promising strategy to counteract skeletal muscle disuse atrophy caused by inactivity. Collectively, the current evidence highlights myostatin as a central molecular integrator of mechanical unloading-induced muscle atrophy.