Here, we report that p16Ink4a-Cdk4-E2F3 signals regulate muscle metabolic function via targeting the mitochondrial biosensor PPARγ coactivator 1-α (PPARGC1A, which encodes to PGC-1α) that is also linked to muscle fiber–type specification and metabolic disease (35–38). This evidence concerns the gene CDK4 and metabolic disease.