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NAD+ centric mechanisms and molecular determinants of skeletal muscle disease and aging

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Abstract

The nicotinamide adenine dinucleotide (NAD+) is an essential redox cofactor, involved in various physiological and molecular processes, including energy metabolism, epigenetics, aging, and metabolic diseases. NAD+ repletion ameliorates muscular dystrophy and improves the mitochondrial and muscle stem cell function and thereby increase lifespan in mice. Accordingly, NAD+ is considered as an anti-oxidant and anti-aging molecule. NAD+ plays a central role in energy metabolism and the energy produced is used for movements, thermoregulation, and defense against foreign bodies. The dietary precursors of NAD+ synthesis is targeted to improve NAD+ biosynthesis; however, studies have revealed conflicting results regarding skeletal muscle-specific effects. Recent advances in the activation of nicotinamide phosphoribosyltransferase in the NAD+ salvage pathway and supplementation of NAD+ precursors have led to beneficial effects in skeletal muscle pathophysiology and function during aging and associated metabolic diseases. NAD+ is also involved in the epigenetic regulation and post-translational modifications of proteins that are involved in various cellular processes to maintain tissue homeostasis. This review provides detailed insights into the roles of NAD+ along with molecular mechanisms during aging and disease conditions, such as the impacts of age-related NAD+ deficiencies on NAD+-dependent enzymes, including poly (ADP-ribose) polymerase (PARPs), CD38, and sirtuins within skeletal muscle, and the most recent studies on the potential of nutritional supplementation and distinct modes of exercise to replenish the NAD+ pool.

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Disclosures

US Patent: 19A039PR [143], USF disclosure, 19A039 (patent pending).

Funding

SMT and MB are partially supported by NIH Grants—National Institutes of Diabetes, Digestive, and Kidney NIDDK-R01DK119066 (SMT, MB). National Institutes of Aging (NIA) 2-PO1AG039355 (MB), NIA-R01AG056504 (MB), and NIA-R01AG060341 (MB). We are thankful for the generous support from the William Saunders Endowed Chair in geriatric Pharmacotherapy (SMT) at University of South Florida. The George W. and Hazel M. Jay and Evanston Research Endowments (MB) and the University of Texas—Arlington College of Nursing and Health Innovation, Bone-Muscle Research Center (https://www.uta.edu/conhi/research/bmrc/index.php). The opinions expressed in this review are solely the authors’ opinions and conclusions and not represent the official opinions and/or endorsement from National Institutes of Health, USF, or UTA.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, USF Health Taneja College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd, MDC 030, Tampa, FL, 33612, USA

    Sabrina Wagner, Ravikumar Manickam & Srinivas M. Tipparaju

  2. Bone-Muscle Research Center, College of Nursing & Health Innovation, University of Texas-Arlington (UTA), Arlington, TX, USA

    Marco Brotto

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  1. Sabrina Wagner
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  2. Ravikumar Manickam
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  3. Marco Brotto
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  4. Srinivas M. Tipparaju
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Contributions

SMT and MB conceptualized the outline and the basis for review. SW and RM provided the initial draft of sections of text and figures. SMT revised, edited, and provided modifications to the draft. SW, RM, MB, and SMT approved the final version of the paper.

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Correspondence to Srinivas M. Tipparaju.

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Wagner, S., Manickam, R., Brotto, M. et al. NAD+ centric mechanisms and molecular determinants of skeletal muscle disease and aging. Mol Cell Biochem 477, 1829–1848 (2022). https://doi.org/10.1007/s11010-022-04408-1

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