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

doi:10.1016/j.cmet.2016.07.005

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

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278 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 language	English (US)
Pages (from-to)	269-282
Number of pages	14
Journal	Cell Metabolism
Volume	24
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2016.07.005
State	Published - 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

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title = "Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle",

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.",

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

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year = "2016",

month = aug,

day = "9",

doi = "10.1016/j.cmet.2016.07.005",

language = "English (US)",

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Frederick, 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 2016, 'Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle', Cell Metabolism, vol. 24, no. 2, pp. 269-282. https://doi.org/10.1016/j.cmet.2016.07.005

TY - JOUR

T1 - Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle

AU - Frederick, David W.

AU - Loro, Emanuele

AU - Liu, Ling

AU - Davila, Antonio

AU - Chellappa, Karthikeyani

AU - Silverman, Ian M.

AU - Quinn, William J.

AU - Gosai, Sager J.

AU - Tichy, Elisia D.

AU - Davis, James G.

AU - Mourkioti, Foteini

AU - Gregory, Brian D.

AU - Dellinger, Ryan W.

AU - Redpath, Philip

AU - Migaud, Marie E.

AU - Nakamaru-Ogiso, Eiko

AU - Rabinowitz, Joshua D.

AU - Khurana, Tejvir S.

AU - Baur, Joseph A.

PY - 2016/8/9

Y1 - 2016/8/9

N2 - 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.

AB - 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.

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JO - Cell Metabolism

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IS - 2

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

Abstract

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