Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle.

TitleLoss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle.
Publication TypeJournal Article
Year of Publication2016
AuthorsFrederick, DW, Loro, E, Liu, L, Davila, A, Chellappa, K, Silverman, IM, Quinn, WJ, 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
JournalCell Metab
Volume24
Issue2
Pagination269-82
Date Published2016 Aug 09
ISSN1932-7420
Abstract

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.

DOI10.1016/j.cmet.2016.07.005
Alternate JournalCell Metab.
PubMed ID27508874
PubMed Central IDPMC4985182
Grant ListP30 AR050950 / AR / NIAMS NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States
R01 AG043483 / AG / NIA NIH HHS / United States
R01 DK098656 / DK / NIDDK NIH HHS / United States