Ageing impairs tissue repair. This defect is pronounced in skeletal muscle, whose regeneration by muscle stem cells (MuSCs) is robust in young-adult animals, but inefficient in older organisms. Despite this functional decline, old MuSCs are amenable to rejuvenation through strategies that improve the systemic milieu, such as heterochronic parabiosis. One such strategy, exercise, has long been appreciated for its benefits on healthspan, but its effects on aged stem-cell function in the context of tissue regeneration are incompletely understood. Here, we show that exercise in the form of voluntary wheel running accelerates muscle repair in old mice and improves old MuSC function. Through transcriptional profiling and genetic studies, we discovered that the restoration of old MuSC activation ability hinges on restoration of Cyclin D1, whose expression declines with age in MuSCs. Pharmacologic studies revealed that Cyclin D1 maintains MuSC activation capacity by repressing TGF-β signalling. Taken together, these studies demonstrate that voluntary exercise is a practicable intervention for old MuSC rejuvenation. Furthermore, this work highlights the distinct role of Cyclin D1 in stem-cell quiescence.

衰老会损害组织修复。这种缺陷在骨骼肌中很明显，肌肉干细胞 (MuSCs) 的再生在年轻成年动物中很强大，但在年长的生物体中效率低下。尽管功能下降，但旧的 MuSC 仍可以通过改善系统环境的策略（例如异慢性联体共生）来恢复活力。其中一种策略，运动，长期以来因其对健康的益处而受到赞赏，但在组织再生的背景下，它对衰老干细胞功能的影响尚不完全清楚。在这里，我们展示了以自愿轮式跑步形式进行的运动可加速老年小鼠的肌肉修复并改善老年 MuSC 功能。通过转录分析和遗传研究，我们发现旧的 MuSC 激活能力的恢复取决于 Cyclin D1 的恢复，其在 MuSCs 中的表达随着年龄的增长而下降。药理学研究表明，Cyclin D1 通过抑制 TGF-β 信号传导来维持 MuSC 激活能力。综上所述，这些研究表明，自愿锻炼是旧肌干细胞再生的一种切实可行的干预措施。此外，这项工作突出了 Cyclin D1 在干细胞静止中的独特作用。