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.

中文翻译：

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烟酰胺和吡哆醇在衰老过程中刺激肌肉干细胞扩增并增强再生能力。


骨骼肌依靠驻留肌肉干细胞 （MuSC） 进行生长和修复。衰老和肌肉疾病会损害 MuSC 功能，导致干细胞耗竭和再生能力下降，从而导致骨骼肌质量和力量的逐渐丧失。在缺乏专门针对 MuSC 的临床可用营养解决方案的情况下，我们使用了食物中天然分子的人类生肌祖细胞 （hMP） 高内涵成像筛选，以识别烟酰胺 （NAM） 和吡哆醇 （PN） 作为刺激 MuSCs 的生物活性营养素，并具有人类安全使用的历史。NAM 和 PN 通过 CK1 介导的细胞质 β-catenin 激活和 AKT 信号传导协同作用，促进 MuSCs 的扩增和分化。口服 NAM/PN 联合治疗通过刺激 MuSCs 加速体内肌肉再生，增加恢复过程中的肌肉力量，并克服衰老过程中的 MuSC 功能障碍和再生衰竭。在模式生物中，NAM 和生物活性 PN 的水平在衰老过程中自发下降，并且在 186 名老年人的人类队列中与肌肉质量和步行速度相互独立相关。总的来说，我们的结果将 NAM/PN 确立为一种新的营养干预措施，可刺激 MuSCs，增强肌肉再生，并缓解与年龄相关的肌肉衰退，并有直接临床转化的机会。