PEROXISOMAL-MITOCHONDRIAL INTERPLAY ALTERATIONS IN SKELETAL MUSCLE RESULT IN EARLY-ONSET SARCOPENIA

Adjustments in muscle mass and metabolic demand are crucial for regulating whole-body metabolism, locomotion, eating, and respiration. Therefore, skeletal muscle is a central influencer of several human diseases. Muscle dysfunction correlates with the onset and progression of several metabolic disorders while improving muscle health with regular exercise reduces morbidity in many conditions. Peroxisomes are ubiquitous dynamic metabolic organelles that play an essential role in various cellular events, such as reactive oxygen species clearance, fatty acid and lipid metabolism and ether phospholipid biosynthesis. However, little is known about their role in muscle metabolism and function. Here, we used a muscle-specific Pex5 KO mouse to investigate the consequences of peroxisomal dysfunction on muscle homeostasis. Our study reveals that peroxisomal impairment triggers early alterations in skeletal muscle lipid and amino acid metabolism and disrupts the physical interaction between peroxisomes and mitochondria, resulting in reduction of muscle force and exercise performance. Over time, these disruptions lead to metabolic changes that affect mitochondrial content, and function anticipating the development of aging sarcopenia. Furthermore, peroxisomal protein levels decline in both mouse and human sarcopenic muscles, and this reduction correlates with muscle dysfunction. Altogether, our findings demonstrate the importance of preserving peroxisomal function and their interaction with mitochondria in maintaining muscle health and innervation during aging.