The effects of exercise on satellite cell dynamics during aging

摘要 老年人虚弱的一个关键决定因素是骨骼肌减少，即与年龄相关的骨骼肌质量下降和 力量。尽管石棺减少症的病因仍有待确定，但对人类和啮齿动物的研究已经 据报道，卫星细胞的丢失和/或功能障碍与骨质疏松症有很强的相关性。尽管 依赖卫星细胞的再生能力下降与年龄之间的相关性，目前还没有研究表明 直接测试了这种关系，以确定卫星细胞的丢失是否会导致骨质疏松症。为了测试这一想法，我们 5个月龄小鼠的卫星细胞耗尽(85%)，显著低于 正常衰老。对24个月大的多块肌肉进行的详细分析显示，尽管 再生能力显著降低，卫星细胞的终生枯竭也没有加速 然而，年轻时卫星细胞的枯竭与 老年小鼠肝纤维化明显增加。这些极具挑衅性的发现，加上我们关于 卫星细胞在运动反应中纤维类型的特定作用，揭示了我们对衰老的有限理解 影响卫星细胞在骨骼肌的维持、纤维化的发生和发展中的作用 对增长刺激的反应；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(Pax7-H2B-GFP)，使我们能够跟踪卫星 首次在成人骨骼肌衰老过程中进行细胞动力学研究。为了更好地了解衰老和锻炼 影响卫星细胞动力学和调节纤维化，将追求以下目标：1)确定 年龄和终生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 对生长刺激的反应影响卫星细胞的动态。这里描述的方法使用 强大的新基因工具来确定衰老和终身锻炼如何改变大脑中卫星细胞的功能 骨骼肌的动态平衡、纤维化的调节和适应性。Pax7-H_2B-GFP的研制 老鼠代表着一种长期受到追捧的追踪卫星细胞的方法，特别是在融合到 肌纤维。这种新的老鼠品系将使我们能够解决有关卫星如何 细胞动力学受年龄和终身锻炼的影响。这样的基本知识对于批判性地 评价卫星细胞治疗肌块丢失及相关功能的价值 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.