NAD Depletion in Skeletal Muscle does not Compromise Muscle Function or Accelerate 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, the extent to which cellular NAD concentration can be decreased without deleterious repercussions is unclear. We generated a mouse model where nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis is disrupted in adult skeletal muscle. The resulting 85% decrease in muscle NAD+ abundance was associated with preserved tissue integrity and functionality, as demonstrated by its unchanged morphology, contractility, and exercise tolerance. This 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 indicate that NAD depletion does not contribute to age related declines in skeletal muscle function.

烟酰胺腺嘌呤二核苷酸（NAD）是一类普遍存在的电子载体，在能量代谢及多种调控蛋白的翻译后修饰过程中发挥关键作用。NAD代谢紊乱被认为有损机体健康，而NAD耗竭通常被认为会加速衰老进程。但目前尚不清楚，在不引发有害后果的前提下，细胞内NAD浓度最多可降低至何种水平。为此，我们构建了一种小鼠模型，可在成年骨骼肌中阻断烟酰胺磷酸核糖转移酶（nicotinamide phosphoribosyltransferase, NAMPT）介导的NAD+生物合成通路。该模型使肌肉NAD+含量降低85%，但肌肉的组织完整性与功能却得以保留：肌肉形态、收缩能力及运动耐力均未出现异常变化。完整的线粒体呼吸功能，以及未发生改变的肌肉转录组与蛋白质组谱，进一步验证了这一无异常表型的存在。此外，终身NAD耗竭并未加速骨骼肌衰老，也未对全身代谢功能造成损害。综上，本研究结果表明，NAD耗竭并不会导致骨骼肌功能随年龄增长而出现衰退。