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Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle
Open accessAbstract
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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“Reduced NAD+ levels in skeletal muscle of aged or Nampt deficient mice alter mitochondrial bioenergetics and impair muscle mass, strength and endurance49,50,52,53”
From Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities (2019) · cites this paper as [52]
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1 retracted
Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats
Braidy, N., Guillemin, G. J., Mansour, H., Chan-Ling, T., Poljak, A., & Grant, R. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019194 · Cited by 594
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Ink4a/Arf expression is a biomarker of aging
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Mouchiroud, L., Houtkooper, R. H., Moullan, N., Katsyuba, E., Ryu, D., Cantó, C., Mottis, A., Jo, Y.-S., Viswanathan, M., Schoonjans, K., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.016 · Cited by 1,210
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Geriatric muscle stem cells switch reversible quiescence into senescence
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Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion
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NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR
Yoshino, J., Baur, J. A., & Imai, S.-I. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.11.002 · Cited by 1,061
“…and NR, Cell Metabolism (2017), https://doi.org/10.1016/j.cmet.2017.11.002 labeled isotopic NR (C13-D-NR) demonstrate that oral NR administration (200 mg/kg) markedly increases circulating nicotinamide concentrations without a major effect on whole-blood NR concentrations (Frederick et al., 2016).”
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NAD+ homeostasis in health and disease
Katsyuba, E., Romani, M., Hofer, D., & Auwerx, J. (2020) · Nature Metabolism · doi:10.1038/s42255-019-0161-5 · Cited by 627
Martens, C. R., Denman, B. A., Mazzo, M. R., Armstrong, M. L., Reisdorph, N., McQueen, M. B., Chonchol, M., & Seals, D. R. (2018) · Nature Communications · doi:10.1038/s41467-018-03421-7 · Cited by 588
Metadata
- Authors
- 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.
- Affiliations
- University of Pennsylvania (US)
- Princeton University (US)
- ChromaDex (United States) (US)
- Queen's University Belfast (GB)
- Corresponding author
- Baur, Joseph A.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 24
- Issue
- 2
- Pages
- 269-282
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4985182
- OpenAlex
- W2499764253
- Cited by
- 367
- References
- 39
- Citations by year
- 2026: 16 · 2025: 43 · 2024: 34 · 2023: 38 · 2022: 49 · 2021: 44 · 2020: 40 · 2019: 39 · 2018: 35 · 2017: 25 · 2016: 4
- FWCI
- 19.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/N001842/1)
- National Institute on Aging (R01AG043483)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK019525, R01DK098656)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR050950, P30AR069619)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- NAD+ homeostasis, skeletal muscle degeneration, visfatin, NAD+ salvage pathway, nicotinamide riboside, muscle fiber degeneration, muscle strength, exercise capacity, aging, muscle mass, NAD+ depletion, genotoxic stress
- MeSH terms
- Administration, Oral, Aging, Animals, Biological Availability, Energy Metabolism, Glucose, Homeostasis, Inflammation, Mice, Inbred C57BL, Mitochondria, NAD, Necrosis, Niacinamide, Organ Size, Physical Conditioning, Animal, Pyridinium Compounds, Transcription, Genetic, Mice, Knockout, Muscle, Skeletal, Muscle Strength, Nicotinamide Phosphoribosyltransferase
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