A need for NAD+ in muscle development, homeostasis, and aging

Roles of NAD+ in skeletal muscle development, homeostasis and aging.


Written by Michelle F. Goody, Clarissa A. Henry

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Skeletal muscle enables posture, breathing, and locomotion. Skeletal muscle also impacts systemic processes such as metabolism, thermoregulation, and immunity. Skeletal muscle is energetically expensive and is a major consumer of glucose and fatty acids. Metabolism of fatty acids and glucose requires NAD+ function as a hydrogen/electron transfer molecule. Therefore, NAD+ plays a vital role in energy production. In addition, NAD+ also functions as a cosubstrate for post-translational modifications such as deacetylation and ADP-ribosylation. Therefore, NAD+ levels influence a myriad of cellular processes including mitochondrial biogenesis, transcription, and organization of the extracellular matrix. Clearly, NAD+ is a major player in skeletal muscle development, regeneration, aging, and disease. The vast majority of studies indicate that lower NAD+ levels are deleterious for muscle health and higher NAD+ levels augment muscle health. However, the downstream mechanisms of NAD+ function throughout different cellular compartments are not well understood. The purpose of this review is to highlight recent studies investigating NAD+ function in muscle development, homeostasis, disease, and regeneration. Emerging research areas include elucidating roles for NAD+ in muscle lysosome function and calcium mobilization, mechanisms controlling fluctuations in NAD+ levels during muscle development and regeneration, and interactions between targets of NAD+ signaling (especially mitochondria and the extracellular matrix). This knowledge should facilitate identification of more precise pharmacological and activity-based interventions to raise NAD+ levels in skeletal muscle, thereby promoting human health and function in normal and disease states.



It is clear that NAD+ plays a beneficial role in muscle health. The mechanisms underlying promotion of muscle development and homeostasis by NAD+ are best understood in the context of sirtuin regulation in the nucleus, mitochondria, and cytosol. The role of NAD+ in other cellular compartments—particularly the vesicular and membrane proximal compartments—in muscle health is currently understudied. Future research will likely delve into not only the mechanisms of NAD+ action in these different compartments but also the interplay and signaling between NAD+ pools within and between cells.