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, Sager J. Gosai, Elisia D. Tichy, James G. Davis, 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

Research output: Contribution to journalArticle

113 Scopus citations

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 (US)
Pages (from-to)269-282
Number of pages14
JournalCell Metabolism
Volume24
Issue number2
DOIs
StatePublished - Aug 9 2016

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Frederick, D. W., Loro, E., Liu, L., Davila, A., Chellappa, K., Silverman, I. M., Quinn, W. J., Gosai, S. J., Tichy, E. D., Davis, J. G., 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