Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle. Mus musculus

NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass, despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function. Overall design: Messenger RNA was isolated from quadriceps muscle of mice from three different age groups and three different genotypes. Wildtype mice were aged 4, 7, and 24 months. Mice deficient for Nampt in skeletal muscle (mNKO) were aged 7 months. Mice overexpressing Nampt in skeletal muscle were aged 4 and 24 months.

烟酰胺腺嘌呤二核苷酸（Nicotinamide Adenine Dinucleotide, NAD）是所有细胞类型中代谢燃料分解代谢的必需辅酶。然而，在基因毒性应激与自然衰老进程中，多种组织内的NAD可用性会出现受限情况。目前尚未明确NAD限制对组织生理功能施加功能性限制的临界节点。本研究通过特异性敲除NAD补救合成途径中的关键酶Nampt（烟酰胺磷酸核糖转移酶，Nicotinamide Phosphoribosyltransferase），在小鼠骨骼肌模型中探究了这一问题。敲除小鼠的肌肉内NAD含量大幅下降85%，同时伴随肌纤维变性、肌肉力量与跑步机耐力进行性丧失。给予NAD前体烟酰胺核糖（nicotinamide riboside）可迅速改善功能缺陷并恢复肌肉质量，尽管其对肌肉内NAD池的影响仅较为温和。此外，终生过表达Nampt可维持老年小鼠的肌肉NAD水平与运动能力，这一结果支持了组织自主性NAD稳态在维持肌肉质量与功能中的关键作用。总体实验设计：从三个不同年龄组与三种不同基因型的小鼠股四头肌中分离信使RNA（messenger RNA, mRNA）。其中，野生型小鼠的年龄分别为4、7和24个月；骨骼肌Nampt缺陷型小鼠（mNKO）的年龄为7个月；骨骼肌过表达Nampt的小鼠年龄分别为4和24个月。