Late‐onset Caloric Restriction Alters Skeletal Muscle Metabolism by Modulating Pyruvate Metabolism

Abstract

Caloric restriction (CR) attenuates age-related muscle loss. However, the underlying mechanism responsible for this attenuation is not fully understood. This study evaluates the role of energy metabolism in the CR-induced attenuation of muscle loss. The aims of this study were three-fold: (1) to evaluate the effects of CR on energy metabolism, (2) to explore if there is a relationship between markers of energy metabolism and muscle mass, and (3) to determine whether the effects of CR are age-dependent. Young and middle-aged rats were randomized into either 40% CR or ad libitum (AL) diet groups for 14 weeks. Major energy-producing pathways in muscles, glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), were examined. We found that the effects of CR were age-dependent. CR improved muscle metabolism and normalized muscle mass in middle-aged animals but not young animals. CR decreased glycolysis and increased the cellular preference for OXPHOS versus glycolysis in muscles of middle-aged rats, which was associated with the improvement of normalized muscle mass. The metabolic re-programming induced by CR was related to modulation of pyruvate metabolism and increased mitochondrial biogenesis. Compared to animals fed AL, middle-aged animals with CR had lower lactate dehydrogenase A content and greater mitochondrial pyruvate carrier content. Markers of mitochondrial biogenesis including AMPK activation levels and SIRT1and COX IV content also increased. In conclusion, 14 weeks of CR improved muscle metabolism and preserved muscle mass in middle-aged animals but not young, developing animals. CR attenuates age-related muscle loss due to reprogramming of metabolic pathway from glycolysis to OXPHOS.