Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway

The maintenance of skeletal muscle mass is critically dependent upon mitochondrial quality control, including balanced mitochondrial dynamics and mitophagy. Dynamin-related protein 1 (Drp1), a key mediator of mitochondrial fission, plays an important role in these processes. However, the precise mechanisms by which Drp1 regulates mitochondrial integrity and muscle mass remain inadequately understood. Here, we show that acute Drp1 deletion from skeletal muscle impairs mitochondrial activity, increases Parkin-mediated mitophagy, progressively reduces mitochondrial DNA (mtDNA) content, and ultimately causes severe muscle atrophy. Interestingly, dual deletion of Drp1 and Parkin from skeletal muscle restored mtDNA content, but did not prevent muscle loss. Mechanistically, Drp1 deletion disrupted mitochondrial respiratory chain activity, which suppressed extracellular signal-regulated kinase 1/2 (Erk1/2) signaling and downregulated the nuclear receptor subfamily 4 group member 1 (Nur77), a regulator of muscle quality. Finally, clenbuterol, a β2-adrenergic receptor agonist, activated Erk1/2 signaling, restored Nur77 expression, and rescued muscle atrophy. Collectively, our findings identify a Drp1-Erk1/2-Nur77 signaling axis that connects mitochondrial integrity to the preservation of skeletal muscle mass and represents a potential therapeutic avenue for muscle degeneration in mitochondrial and metabolic disorders.