NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging
Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD<sup>+</sup> biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD<sup>+</sup> abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.
Authors
- Juleen Rae Zierath (ORCID: https://orcid.org/0000-0001-6891-7497)
- Ondřej Hodek (ORCID: https://orcid.org/0000-0001-8307-9575)
- Danial Ahwazi (ORCID: https://orcid.org/0000-0003-2747-2684)
- Amy M. Ehrlich (ORCID: https://orcid.org/0000-0003-4830-1024)
- Caio Yogi Yonamine (ORCID: https://orcid.org/0000-0002-9884-8258)
- Kei Sakamoto (ORCID: https://orcid.org/0000-0001-8839-5980)
- Ben Stocks (ORCID: https://orcid.org/0000-0002-9281-0793)
- Thomas E. Jensen (ORCID: https://orcid.org/0000-0001-6139-8268)
- Daniela Giustarini (ORCID: https://orcid.org/0000-0003-4929-5316)
- Samuel R. Heaselgrave
- Jonas T. Treebak (ORCID: https://orcid.org/0000-0003-1488-7012)
- Astrid Linde Basse (ORCID: https://orcid.org/0000-0002-6532-9232)
- Kajetan Trôst (ORCID: https://orcid.org/0000-0002-3863-5269)
- Nils Joakim Færgeman (ORCID: https://orcid.org/0000-0002-9281-5287)
- Raíssa Mansilla (ORCID: https://orcid.org/0000-0002-2519-0811)
- Iuliia E. Karavaeva (ORCID: https://orcid.org/0000-0003-2450-2585)
- Gareth G. Lavery (ORCID: https://orcid.org/0000-0001-5794-748X)
- Carlos Henríquez‐Olguín (ORCID: https://orcid.org/0000-0002-9315-9365)
- Ivan Kulik (ORCID: https://orcid.org/0000-0001-9033-1839)
- Thomas Möritz (ORCID: https://orcid.org/0000-0002-4258-3190)
- Emilie Dalbram (ORCID: https://orcid.org/0000-0002-7679-5896)
- Zachary Gerhart‐Hines (ORCID: https://orcid.org/0000-0003-2981-4991)
- Ranieri Rossi (ORCID: https://orcid.org/0000-0002-0187-4530)
- Atul S. Deshmukh (ORCID: https://orcid.org/0000-0002-2278-1843)
- Jesper Foged Havelund (ORCID: https://orcid.org/0000-0002-9797-5431)
- Sabina Chubanava (ORCID: https://orcid.org/0000-0002-5842-2623)
- Farina Schlabs
- Steen Larsen
- Roger M. Justicia
Institutions
- University of Siena (IT)
- University of Copenhagen (DK)
- Medical University of Białystok (PL)
- University of Southern Denmark (DK)
- Novo Nordisk Foundation (DK)
- Swedish University of Agricultural Sciences (SE)
- Helmholtz Zentrum München (DE)
- Finis Terrae University (CL)
- University of Birmingham (GB)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1016/j.cmet.2025.04.002
- Citations
- 16
- Primary Topic
- Sirtuins and Resveratrol in Medicine
- Type
- article
- Field-Weighted Citation Impact
- 19.58
Funders
- Wellcome Trust
- Novo Nordisk Fonden