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

David W. Frederick, Emanuele Loro, Ling Liu, Antonio Davila, Karthikeyani Chellappa, Ian M. Silverman, William J. Quinn III, Sager J. Gosai, Elisia D. Tichy, Foteini Mourkioti, Brian D. Gregory, Ryan W. Dellinger, Philip Redpath, Marie E. Migaud, Eiko Nakamaru-Ogiso, Joshua D. Rabinowitz, Tejvir S. Khurana, Joseph A. Baur*

*Corresponding author for this work

Research output: Contribution to journalArticle

116 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)269-282
Number of pages14
JournalCell metabolism
Volume24
Issue number2
DOIs
Publication statusPublished - 09 Aug 2016

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Frederick, D. W., Loro, E., Liu, L., Davila, A., Chellappa, K., Silverman, I. M., Quinn III, W. J., Gosai, S. J., Tichy, E. D., Mourkioti, F., Gregory, B. D., Dellinger, R. W., Redpath, P., Migaud, M. E., Nakamaru-Ogiso, E., Rabinowitz, J. D., Khurana, T. S., & Baur, J. A. (2016). Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle. Cell metabolism, 24(2), 269-282. https://doi.org/10.1016/j.cmet.2016.07.005