Exercise and caloric restriction (CR) significantly increase longevity across a range of species and delay aging-related losses in organ function. Although both interventions enhance skeletal muscle function, the molecular mechanisms underlying these associations are unknown. We sought to identify genes regulated by CR and exercise in muscle, and investigate their relationship with muscle function. To do this, expression profiles of Gene Expression Omnibus datasets obtained from the muscle tissue of calorie-restricted male primates and young men post-exercise were analyzed. There were seven transcripts (ADAMTS1,CPEB4,EGR2, IRS2,NR4A1,PYGO1, andZBTB43) that were consistently upregulated by both CR and exercise training. We used C2C12 murine myoblasts to investigate the effect of silencing these genes on myogenesis, mitochondrial respiration, autophagy, and insulin signaling, all of which are processes affected by CR and exercise. Our results show that in C2C12 cells,Irs2andNr4a1expression were critical for myogenesis, and five genes (Egr2,Irs2,Nr4a1,Pygo1, andZBTB43) regulated mitochondrial respiration while having no effect on autophagy.Cpeb4knockdown increased the expression of genes involved in muscle atrophy and induced myotube atrophy. These findings suggest new resources for studying the mechanisms underlying the beneficial effects of exercise and calorie restriction on skeletal muscle function and lifespan extension.