Exercise as a Bidirectional Regulator of Drp1: A Goldilocks Principle for Mitochondrial Adaptation in Skeletal Muscle

Dynamin-related protein 1 (Drp1) is essential for mitochondrial dynamics in skeletal muscle, particularly in regulating fission, mitophagy, and maintaining mitochondrial function. Exercise is crucial for sustaining muscle function, promoting mitochondrial adaptations that enhance energy metabolism and oxidative capacity in skeletal muscle. In this Review, we discuss the role of Drp1 in exercise-induced mitochondrial adaptations and its potential implications for skeletal muscle health. We first address the evidence that Drp1 activity must be maintained within a narrow physiological range. Both Drp1 deficiency and overabundance provoke muscle atrophy and dysfunction, establishing a Goldilocks principle for mitochondrial fission. We then examine the multi-layered post-translational modification code that governs Drp1 activity, including canonical phosphorylation, redox-sensing modifications, and the receptor selectivity model that may specify distinct fission programs. A three-stage model of exercise-induced mitochondrial adaptation is presented, describing how Drp1 activity is temporally orchestrated from acute fragmentation through short-term remodeling to long-term network optimization, and how these morphological transitions govern substrate metabolism and determine exercise performance. The pathological consequences of Drp1 dysregulation are examined in metabolic disease, where Drp1 is chronically hyperactivated, and in aging, where Drp1 activity is deficient. Finally, we analyze the ROS-Drp1 signaling axis as the mechanistic basis for the bidirectional regulation of Drp1 by exercise. Moderate exercise-induced ROS production activates Nrf2 and AMPK signaling, which suppress excessive fission in metabolic disease while restoring insufficient fission in aging, thereby moving Drp1 activity toward the physiological Goldilocks zone in both contexts. This context-dependent, bidirectional regulation distinguishes exercise from pharmacological inhibitors and identifies the ROS-Drp1 axis as a therapeutic target for conditions at opposite ends of the Drp1 activity continuum, such as sarcopenia and type 2 diabetes.