Brett Jamie O, Arjona Marina, Ikeda Mika, Quarta Marco, de Morrée Antoine, Egner Ingrid M, Perandini Luiz A, Ishak Heather D, Goshayeshi Armon, Benjamin Daniel I, Both Pieter, Rodríguez-Mateo Cristina, Betley Michael J, Wyss-Coray Tony, Rando Thomas A
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
Nat Metab. 2020 Apr;2(4):307-317. doi: 10.1038/s42255-020-0190-0. Epub 2020 Apr 13.
Aging impairs tissue repair. This 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 animals 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 TGFβ signaling. 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。这在骨骼肌中表现得尤为明显，在年轻成年动物中，肌肉干细胞（MuSCs）对骨骼肌的再生能力很强，但在老年生物中则效率低下。尽管功能有所下降，但通过改善全身环境的策略，如异时联体共生，老年MuSCs仍可恢复活力。运动就是这样一种策略，长期以来人们一直认识到它对健康寿命有益，但其在组织再生背景下对衰老干细胞功能的影响尚未完全了解。在这里，我们表明，以自愿轮转跑步形式进行的运动可加速老年动物的肌肉修复并改善老年MuSCs的功能。通过转录谱分析和基因研究，我们发现老年MuSCs激活能力的恢复取决于细胞周期蛋白D1（Cyclin D1）的恢复，其在MuSCs中的表达会随着年龄的增长而下降。药理学研究表明，Cyclin D1通过抑制TGFβ信号传导来维持MuSCs的激活能力。综上所述，这些研究表明自愿运动是一种可行的干预老年MuSCs恢复活力的方法。此外，这项工作突出了Cyclin D1在干细胞静止中的独特作用。
