NAD+ repletion via NMN or NR shows context-dependent effects on muscle stem cell homeostasis and sarcopenia

Photo by Jason Dent / Unsplash

Frontiers in Medicine Published June 5, 2026 Medically reviewed June 5, 2026 DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Note developing NAD+-targeted therapies for sarcopenia remain a hypothesis-driven framework with current inconsistencies.

This systematic review evaluates the role of NAD+ repletion via precursors such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) in addressing sarcopenia. The analysis covers nearly 60 representative preclinical and clinical studies to explore the dual-function nature of NAD+ signaling on muscle stem cells.

Moderate NAD+ repletion activates SIRT1 and SIRT3, which enhances mitochondrial bioenergetics and reduces oxidative stress. These mechanisms promote muscle stem cell proliferation and myogenic differentiation. However, excessive or dysregulated NAD+ signaling activates SIRT2 to deacetylate PAX7 and repress Myogenic Differentiation 1 (MyoD). This pathway leads to cell-cycle arrest and muscle stem cell exhaustion.

The review highlights secondary outcomes including MuSC quiescence, MuSC proliferation, MuSC differentiation, myogenic differentiation, cell-cycle arrest, MuSC exhaustion, mitochondrial bioenergetics, and oxidative stress. The authors acknowledge current inconsistencies in the field as a primary limitation. Consequently, the practice relevance is described as developing NAD+-targeted therapies for sarcopenia within a hypothesis-driven framework.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedJun 2026

View Original Abstract ↓

Sarcopenia is an age-related syndrome characterized by progressive loss of skeletal muscle mass and function, which is closely associated with impaired regenerative capacity of muscle satellite cells (MuSCs). During aging, the MuSC niche undergoes severe deterioration, including mitochondrial dysfunction, chronic inflammation, and neuromuscular junction (NMJ) degeneration, all of which compromise MuSC quiescence, proliferation, and differentiation.Nicotinamide adenine dinucleotide (NAD+) serves as a critical coenzyme and signaling molecule that governs MuSC homeostasis in a context-dependent, dual-function manner. Moderate NAD+ repletion via precursors such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) activates SIRT1 and SIRT3, enhances mitochondrial bioenergetics, reduces oxidative stress, and promotes MuSC proliferation and myogenic differentiation. In contrast, under pathological or aging conditions, excessive or dysregulated NAD+ signaling activates SIRT2 to deacetylate PAX7 and repress Myogenic Differentiation 1 (MyoD), leading to cell-cycle arrest and MuSC exhaustion.This review adopts a hypothesis-driven framework to systematically summarize the molecular crosstalk between NAD+ metabolism, sirtuin family deacetylases (SIRTs), and MuSC fate regulation. We integrate evidence from nearly 60 representative preclinical and clinical studies, clarify the dual-function role of NAD+, and address current inconsistencies in the field. We also highlight key limitations and propose future directions for developing NAD+-targeted therapies for sarcopenia.