The Anti-Aging Role of Klotho in Skeletal Muscle Regeneration

摘要： 与年龄相关的衰老肌肉再生能力的损害是导致 功能活动能力下降，并与老年人口发病率增加有关。跟随 急性损伤时，年轻的骨骼肌启动高效的再生反应，这种反应在很大程度上可以恢复 受损纤维的原始结构。相反，随着年龄的增长，对 损伤导致相当大的疤痕组织沉积，损害功能性收缩组织。大部分 这种愈合缺陷被归因于与年龄相关的肌肉干细胞或卫星细胞(MUSC)的减少 功能性。作为对骨骼肌损伤的反应，MuSCs从静止状态变为激活以进行修复 肌纤维受损。然而，有研究表明，损伤后纤维化沉积的增加是一种 MSC由肌源性向纤维性转化和细胞衰老的结果。幸运的是，这些年龄- 相关变化是可逆的。优雅的研究使用了异慢性异型共生，其中循环 幼年和老年动物的系统是相连的，已经揭示了系统的年轻化 微环境显著恢复了衰老肌肉的整体组织再生能力和MUSC再生能力。 这些发现暗示，循环因子，如Klotho，在决定骨骼肌的过程中起着关键作用 随着时间的推移，再生潜力。阐明了造成这一现象的循环因素的来源和性质 衰老的肌肉表型对于制定预防、延缓或逆转年龄相关的策略至关重要 下降了。 与FOA的目标一致，这项研究的首要目标是确定 抗老年蛋白Klotho，在调节肌肉愈合能力随年龄增长而下降的过程中，以及 机械地检验我们的假设，即与年龄相关的神经肌肉活动的下降有助于减弱 Klotho表情。具体地说，在目标1中，我们将询问Klotho 表达调控MUSC线粒体功能和骨骼肌再生潜能。在目标2中，我们将 确定收缩活动刺激Klotho表达和促进的分子机制 肌肉愈合。 这些研究一旦完成，将对实地产生长期和持久的影响，因为它们将确立 Klotho是一种重要的抗老年因子，调节功能性肌肉所必需的MUSC活性 受伤后的再生。此外，这些实验还将为今后的研究奠定基础 老年人群中的肌肉刺激可用于预防、延缓或逆转与年龄相关的 通过提高再生能力来实现肌肉功能。

ABSTRACT: An age-related impairment of the regenerative capacity of aged muscle is a major contributor to declines in functional mobility and is associated with an increased morbidity in an elderly population. Following an acute injury, young skeletal muscle initiates a highly effective regenerative response, which largely restores the original architecture of the damaged fibers. Conversely, with increasing age, the regenerative response to injury results in a considerable scar tissue deposition at the expense of functional contractile tissue. Much of this healing defect has been attributed to an age-related decrease in muscle stem, or satellite, cell (MuSC) functionality. In response to skeletal muscle injury, MuSCs become activated from a quiescent state to repair damaged myofibers. However, it has been suggested that the increased fibrosis deposition following injury is a result of a myogenic-to-fibrogenic conversion and cellular senescence of MuSCs. Fortunately, these age- related changes are reversible. Elegant studies employing heterochronic parabiosis, in which the circulatory systems of young and aged animals are conjoined, have revealed that rejuvenation of the systemic microenvironment significantly restores both whole tissue and MuSC regenerative capacity in aged muscle. These findings implicate that circulating factors, such as Klotho, play a critical role in dictating skeletal muscle regenerative potential over time. Elucidation of the origin and nature of circulating factors contributing to the aged muscle phenotype is critical for the development of strategies to prevent, delay or reverse age-related declines. Consistent with the objective of the FOA, the overarching goal of this study is to identify a novel role for the anti-geronic protein, Klotho, in mediating declines in muscle healing capacity with increasing age, and to mechanistically test our hypothesis that age-related declines in neuromuscular activity contribute to attenuated Klotho expression. Specifically, in Aim 1, we will interrogate the underlying mechanism by which Klotho expression regulates MuSC mitochondrial function and skeletal muscle regenerative potential. In Aim 2, we will define the molecular mechanisms by which contractile activity stimulates Klotho expression and promotes muscle healing. These studies, when completed, will have a long and lasting impact on the field as they will establish Klotho as an important anti-geronic factor that regulates MuSC activity essential for functional muscle regeneration after injury. In addition, these experiments will lay the groundwork for future studies in which muscle stimulation in geriatric populations may be used to prevent, delay or reverse age-related declines in muscle function through improved regenerative capacity.