ABSTRACT: Skeletal muscle function is vital to movement, thermogenesis and metabolism. Muscle fibers differ in contractile ability, mitochondrial content and metabolic properties and muscle fiber transition influences muscle function. However, the molecular mechanisms regulating muscle fiber transition in muscle function are unclear. Here, in over 150 human muscle samples, we observed that markers of oxidative muscle fiber and mitochondria correlate positively with PPARGC1 and CDK4, and, negatively with CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing an overactive Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, are longer, leaner, exhibit increased oxidative myofibers with superior mitochondrial energetics, display enhanced muscle glucose uptake, and are protected from obesity and diabetes. In contrast, Cdk4-deficiency, or skeletal muscle-specific deletion of Cdk4’s transcriptional target, E2F3, reduces oxidative myofiber numbers, deteriorates mitochondrial function and exercise capacity, while increasing diabetes susceptibility. E2F3 activates the PPARGC1 promoter and CDK4/E2F3/PPARGC1 levels correlate positively with exercise and fitness, and negatively with adiposity, insulin resistance and lipid accumulation in muscle. These findings provide insight into oxidative muscle fiber transition and function that is of relevance to metabolic and muscular diseases.
