Beyond Mitochondrial Fission: Emerging Roles of Drp1 in Skeletal Muscle Physiology and Disease

Dynamin-related protein 1 (Drp1) is best recognized as the primary regulator of mitochondrial fission. However, emerging evidence indicates that Drp1 is a multifaceted regulator of skeletal muscle physiology whose functions extend well beyond its canonical role in mitochondrial fission. Recent studies have identified novel roles of Drp1 in regulating substrate utilization, calcium homeostasis, reactive oxygen species signaling, respiratory complex assembly, and mitochondrial-to-nuclear signaling, including mechanisms independent of its canonical fission activity. Importantly, Drp1 regulation in skeletal muscle is highly context-dependent, as both excessive and insufficient Drp1 activity can disrupt skeletal muscle homeostasis. For example, excessive Drp1 activation and mitochondrial fragmentation are associated with insulin resistance, type 2 diabetes, and neuromuscular diseases, whereas severe or prolonged Drp1 deficiency impairs mitochondrial quality control, bioenergetics, induce muscle atrophy, and compromise the exercise training adaptations. Therefore, the biological consequences of Drp1 modulation are highly context dependent and influenced by the metabolic and physiological state of skeletal muscle. In this review, we summarize the molecular regulation and emerging functions of Drp1 in skeletal muscle, with particular emphasis on fission-independent mechanisms and Drp1 dysregulation in metabolic and neuromuscular diseases. We further discuss pharmacological and non-pharmacological strategies for modulating Drp1 signaling and highlight emerging approaches for skeletal muscle-specific targeting. Collectively, current evidence supports a paradigm in which skeletal muscle Drp1 functions as a multifaceted regulator of mitochondrial and skeletal muscle homeostasis, highlighting the therapeutic potential of modulating Drp1 activity to optimize mitochondrial and muscle health across different physiological and pathological contexts.