Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging.

Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor (hMP) high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM/PN accelerates muscle regeneration in vivo by stimulating MuSCs, increases muscle strength during recovery, and overcomes MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously decline during aging in model organisms and inter-independently associate with muscle mass and walking speed in a human cohort of 186 aged people. Collectively, our results establish NAM/PN as a new nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.