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

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.

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

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

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.

The laws of thermodynamics state that energy remains constant within a closed system. Energy is neither created nor destroyed; it just changes form. In biology, the flow of energy through organisms, tissues, and cells is a universal requirement to sustain life. Energy in the form of dietary nutrients is metabolized into adenosine triphosphate (ATP) and other molecules that power necessary cellular processes. Therefore, energy is potentially the most important information that cells interpret. As such, it would logically follow that multiple, highly nuanced cellular mechanisms for nutrient and energy sensing would evolve due to intense selective pressures. This exquisite tailoring of form to function is perhaps best exemplified in the mitochondrial reticulum that facilitates quick energy transfer throughout the muscle cell [1]. Oxidized nicotinamide adenine dinucleotide (NAD+) and its reduced form, reduced nicotinamide adenine dinucleotide (NADH), are critical molecules involved in energy generation because NAD+/NADH participate in oxidation-reduction (redox) reactions in the tricarboxylic acid (TCA) cycle. In this context, NAD+ is not destroyed, it is reversibly reduced. However, NAD+ is also a cosubstrate in multiple post-translational modifications such as deacetylation and ADP-ribosylation. These reactions result in consumption of NAD+, necessitating replenishment of cellular NAD+ stores. Thus, maintaining the balance between NAD+ degradation and biosynthesis is extremely important for cellular homeostasis. In this review, we will discuss evidence and mechanisms of NAD+ function in skeletal muscle development, homeostasis, and disease.

In addition to mediating posture and locomotion, skeletal muscle is a metabolically important organ. Skeletal muscles sense, produce, store, and utilize nutrients and energy transfer molecules that enable muscle to participate in systemic, energy-expensive processes such as temperature regulation and immunity. Skeletal muscle is plastic and readily adapts to change. Examples of skeletal muscle plasticity include hypertrophy in response to weight bearing exercise, atrophy in response to disuse, and fiber type switching due to changes in gene expression, cellular metabolism, or innervation. It seems likely that there is coordination between skeletal muscle’s energy use/sensing and the signaling pathways that regulate its remarkable phenotypic plasticity.

Muscle diseases have a negative effect on health, lifespan, and/or quality of life. Genetic muscle diseases caused by mutations result in a variety of ultrastructural defects in muscle cells and progressive loss of muscle mass and function via multiple different mechanisms. Inflammatory or metabolic diseases (such as diabetes, obesity, autoimmune diseases, cancer, and infections) can result in loss of skeletal muscle as well. Given the integration and interdependence of the nervous and muscular systems, neural disorders or injuries can also impair muscle tissue structure and function. Additionally, skeletal muscle is lost as a natural part of the aging process, and this loss is exacerbated in a condition called sarcopenia. Adequate skeletal muscle mass prior to illness, injury, or aging is predictive of recovery and healthy aging (reviewed in [2]). Skeletal muscle performs a diverse set of crucial functions in organisms and promoting muscle health and exploiting its plasticity could improve locomotion, metabolism, and quality of life in many disorders.

While NAD+ can cycle between its oxidized and reduced forms in redox reactions, it is cleaved when it functions as a cosubstrate. Thus, NAD+ must be constantly re-synthesized from dietary precursors in order to maintain cellular pools of NAD+ as well as appropriate NAD+/NADH ratios. It is not entirely clear whether the critical aspect of NAD+ biology in skeletal muscle is levels of NAD+ or the NAD+/NADH ratio [4]. For simplicity, we will generally just refer to NAD+ levels.

Periods of muscle development and/or growth may be coordinated with nutrient availability. As NAD+ provides cells with information about nutrient levels, it is likely that NAD+ is involved in regulating these cellular transitions. A decrease in NAD+ levels is observed in myotubes compared to myoblasts (both in C2C12s and primary muscle cells) [34]. Thus, the current thinking is that decreased NAD+ levels are permissive for muscle differentiation. 

NAD+ levels are reduced in aged muscle in rats, mice, and humans [9, 54, 55], leading to reduced SIRT1 activity, and reduced mitochondrial homeostasis. The mechanisms by which NAD+ levels are modulated are of extreme interest because understanding these mechanisms could lead to approaches to slow or even halt the loss of muscle mass and function during aging. Here, we will discuss recent insights into the mechanisms underlying decreased NAD+ with aging and highlight interventions that increase NAD+ and skeletal muscle function.

Skeletal muscle mass and function are not only critical for daily life but also whole-body protein metabolism and thus play a critical role in metabolic diseases such as obesity and type 2 diabetes (reviewed in [2]). Metabolic diseases are common and debilitating conditions. Given the roles of skeletal muscle and NAD+ in metabolic regulation, it is possible that NAD+ supplementation could improve metabolic health.

Michelle F. Goody & Clarissa A. Henry  Skeletal Muscle volume 8, Article number: 9 (2018)