Abstract
Skeletal muscle, constituting 40-50% of total body mass, is vital for mobility, posture, and systemic homeostasis. Muscle contraction heavily relies on ATP, primarily generated by mitochondrial oxidative phosphorylation. Mitochondria play a key role in decoding intracellular calcium signals. The endocannabinoid system (ECS), including CB(1) receptors (CB(1)Rs), broadly influences physiological processes and, in muscles, regulates functions like energy metabolism, development, and repair. While plasma membrane CB(1)Rs (pCB(1)Rs) are well-established, a distinct mitochondrial CB(1)R (mtCB(1)R) population also exists in muscles, influencing mitochondrial oxidative activity and quality control. We investigated the role of mtCB(1)Rs in skeletal muscle physiology using a novel systemic mitochondrial CB(1) deletion murine model. Our in vivo studies showed no changes in motor function, coordination, or grip strength in mtCB(1) knockout mice. However, in vitro force measurements revealed significantly reduced specific force in both fast-twitch (EDL) and slow-twitch (SOL) muscles following mtCB(1)R ablation. Interestingly, knockout EDL muscles exhibited hypertrophy, suggesting a compensatory response to reduced force quality. Electron microscopy revealed significant mitochondrial morphological abnormalities, including enlargement and irregular shapes, correlating with these functional deficits. High-resolution respirometry further demonstrated impaired mitochondrial respiration, with reduced oxidative phosphorylation and electron transport system capacities in knockout mitochondria. Crucially, mitochondrial membrane potential dissipated faster in mtCB(1) knockout muscle fibers, whilst mitochondrial calcium levels were higher at rest. These findings collectively establish that mtCB(1)Rs are critical for maintaining mitochondrial health and function, directly impacting muscle energy production and contractile performance. Our results provide new insights into ECS-mediated regulation of skeletal muscle function and open therapeutic opportunities for muscle disorders and aging.