Perilipin 5 enhances glycogen storage and mitigates excessive fatty acid oxidation in skeletal muscle to alleviate mitochondrial impairment.

Perilipin 5 (Plin5) is a lipid droplet-associated protein that regulates lipid hydrolysis and mitochondrial oxidative metabolism, and is highly expressed in skeletal muscle. Its role in skeletal muscle glucose metabolism and its relevance to mitochondrial myopathy (MM) remain unclear. We used Plin5-knockout (Plin5-KO) mice in exhaustive swimming tests to assess endurance and anaerobic exercise capacity. Glucose uptake was measured using 2-NBDG; glucose, lactate, NADH/NAD+ ratio, and fatty acid oxidation (FAO) rate were determined with commercial kits. Mitochondrial ultrastructure was evaluated via electron microscopy, and immunoblotting was used to assess proteins related to glucose-lipid metabolism. Muscle biopsies from 26 patients with mitochondrial myopathy were examined morphologically and for Plin5 expression by immunohistochemistry. Plin5-KO mice showed impaired anaerobic capacity, markedly reduced glycogen storage (especially after-exercise), increased lactate production, and reduced AKT phosphorylation, indicating insulin resistance. Mechanistically, Plin5 deficiency promoted excessive FAO, worsened mitochondrial damage, and elevated the NADH/NAD+ ratio, shifting glucose metabolism toward anaerobic glycolysis with excess lactate output. In contrast, Plin5 overexpression improved insulin sensitivity and reduced FAO in skeletal muscle cells. In MM patients, Plin5 expression in skeletal muscle tended to be negatively associated with blood lactate levels. These findings indicate that Plin5 may play a crucial role in improving glycolipid metabolism and protecting mitochondrial function by enhancing glycogen storage and reducing excessive FAO in skeletal muscle cells.