Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle.
Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle.
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DOI：
10.1016/j.cmet.2016.07.005
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发表时间：
2016-08-09
期刊：
影响因子：
29
通讯作者：
Baur JA
中科院分区：
文献类型：
--
作者：
Frederick DW;Loro E;Liu L;Davila A Jr;Chellappa K;Silverman IM;Quinn WJ 3rd;Gosai SJ;Tichy ED;Davis JG;Mourkioti F;Gregory BD;Dellinger RW;Redpath P;Migaud ME;Nakamaru-Ogiso E;Rabinowitz JD;Khurana TS;Baur JA
NAD是所有细胞类型中代谢燃料催化剂的专性辅因子。然而，在遗传毒性应激和自然衰老过程中，几种组织中NAD的可用性可能会受到限制。NAD限制对组织生理学的功能限制点仍然未知。我们在小鼠骨骼肌中通过特异性删除NAD补救途径中的一种必需酶Nampt来研究这个问题。基因敲除小鼠表现出肌肉内NAD含量急剧下降85%，伴随着纤维变性和肌肉力量和跑步机耐力的逐渐丧失。给予NAD前体烟酰胺核苷迅速改善功能缺陷并恢复肌肉质量，尽管对肌内NAD库仅具有适度的影响。此外，Nampt的终身过表达保留了老年小鼠的肌肉NAD水平和运动能力，支持组织自主NAD稳态在维持肌肉质量和功能中的关键作用。随着年龄的增长或疾病的发生，多种组织中的NAD水平下降。Frederick等人表明，受损的肌内NAD合成会随着时间的推移损害骨骼肌质量和强度，但可以通过口服NAD前体快速恢复。NAD补救途径的上调保护了老年小鼠的运动表现。
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 deleting 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. NAD levels decline in multiple tissues with age or in disease. Frederick et al. show that impaired intramuscular NAD synthesis compromises skeletal muscle mass and strength over time but can be quickly restored with an oral NAD precursor. Upregulation of the NAD salvage pathway preserves exercise performance in aged mice.