The effects of exercise on satellite cell dynamics during aging

摘要 老年虚弱的一个关键决定因素是肌肉减少症，即与年龄相关的骨骼肌质量损失， 实力虽然肌肉减少症的病因仍有待确定，但在人类和啮齿动物中的研究已经证实了这一点。 报道了卫星细胞的损失和/或功能障碍与肌肉减少症之间的强相关性。尽管 卫星细胞依赖性再生能力下降与年龄之间的相关性，迄今为止还没有研究表明 直接测试了这种关系，以确定卫星细胞的丢失是否会导致肌肉减少症。为了验证这个想法，我们 在5个月大的小鼠中，卫星细胞被耗尽（>85%）至显著低于用 正常老化。对24个月大的多块肌肉的详细分析显示，尽管 再生能力显著降低，卫星细胞的终身耗尽并没有加速， 加剧肌肉减少症;然而，年轻时卫星细胞的耗竭与 老年小鼠纤维化显著增加。这些极具挑衅性的发现，加上我们关于 纤维型卫星细胞对运动的反应的特定作用，揭示了我们对衰老的有限认识 影响卫星细胞在骨骼肌维持、纤维化发展和免疫中的功能 应对增长刺激;解决我们知识中的这些根本差距显然需要新的 工具.为此，我们将利用一种新的小鼠品系（Pax 7-H2 B-GFP），这将使我们能够跟踪卫星 细胞动力学首次在成人骨骼肌老化。为了更好地了解衰老和运动 影响卫星细胞动力学和纤维化的调节，将追求以下目标：1）确定 年龄和终身锻炼如何影响骨骼肌维持中的卫星细胞动力学，2） 确定年龄和终身锻炼如何影响纤维化的卫星细胞调节，以及3）确定年龄如何影响纤维化的卫星细胞调节。 影响卫星细胞对生长刺激的反应动力学。本文描述的方法使用 强大的，新的遗传工具，以确定如何老化和终身运动改变卫星细胞的功能， 骨骼肌稳态、纤维化调节和适应性。Pax 7-H2 B-GFP的开发 小鼠代表了一种长期寻求的跟踪卫星细胞的方法，特别是在融合到 肌纤维这种新的小鼠品系将使我们能够正式解决棘手的问题， 细胞动力学受到年龄和终生锻炼的影响。这些基本知识对于批判性地 评估卫星细胞对治疗肌肉质量损失和功能相关疾病的治疗价值， 随着年龄的增长。

Abstract A key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletal muscle mass and strength. Although the etiology of sarcopenia remains to be determined, studies in humans and rodents have reported a strong correlation between the loss and/or dysfunction of satellite cells and sarcopenia. Despite the correlation between declining satellite cell-dependent regenerative capacity and age, no studies to date have directly tested this relationship to determine if the loss of satellite cells causes sarcopenia. To test this idea, we depleted (>85%) satellite cells in five month old mice to a level dramatically lower than that observed with normal aging. A detailed analysis of multiple muscles through 24 months of age revealed that, despite significantly reduced regenerative capacity, the life-long depletion of satellite cells did not accelerate nor exacerbate sarcopenia; however, the depletion of satellite cells at a young age was associated with a significant increase in fibrosis in old mice. These highly provocative findings, together with our data on the fiber-type specific role of satellite cells in response to exercise, reveal our limited understanding of how aging affects the function of satellite cells in skeletal muscle maintenance, the development of fibrosis and in response to a growth stimulus; addressing these fundamental gaps in our knowledge clearly requires new tools. Towards this end, we will utilize a novel mouse strain (Pax7-H2B-GFP) that will allow us to track satellite cell dynamics for the first time in adult skeletal muscle aging. To better understand how aging and exercise affects satellite cell dynamics and the regulation of fibrosis, the following aims will be pursued: 1) determine how age and life-long exercise affects satellite cell dynamics in the maintenance of skeletal muscle, 2) determine how age and life-long exercise affects satellite cell regulation of fibrosis and 3) determine how age affects satellite cell dynamics in response to a growth stimulus. The approaches described herein use powerful, new genetic tools to determine how aging and life-long exercise alters the function of satellite cells in skeletal muscle homeostasis, regulation of fibrosis and adaptability. The development of the Pax7-H2B-GFP mouse represents a long sought-after method for tracking satellite cells, especially following fusion into the myofiber. This novel mouse strain will allow us to address formally intractable questions regarding how satellite cell dynamics are affected by age and life-long exercise. Such fundamental knowledge is necessary to critically evaluate the therapeutic value of satellite cells for the treatment of muscle mass loss and function associated with aging.