Skeletal Muscle NAD Depletion Does Not Accelerate Muscle Aging

NAD is a ubiquitous electron carrier essential for energy metabolism and the post-translational modification of numerous regulatory proteins. Perturbation of NAD metabolism is considered detrimental to health, with NAD depletion commonly thought to promote aging. However, to what extent normal NAD concentration can be decreased without deleterious repercussions is unclear. Here, we describe a mouse model where NAMPT-mediated NAD+ biosynthesis is disrupted in adult skeletal muscle. The resulting 85% decrease in muscle NAD+ abundance did not cause tissue degeneration or dysfunction, as reflected in its unchanged morphology, contractility, and exercise tolerance. The lack of defects was corroborated by intact mitochondrial respiratory capacity and unaffected muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings demonstrate that NAD depletion does not drive the age-related decline in skeletal muscle function.