Regulation of Skeletal Muscle Regeneration During Aging by Growth Differentiation Factor 11

 描述(申请人提供)：骨骼肌是一种高度组织化的组织，其功能是支持身体的运动和运动。在整个成年生活中，骨骼肌经历了一个强有力的组织再生过程，以应对损伤，但这一过程的有效性在老年时显著下降。这种与年龄相关的骨骼肌功能障碍对老年人的健康构成了重大的担忧，以至于肌肉修复不足。 会导致肌肉质量下降、力量丧失和生活质量受损。因此，开发新的治疗方法来预防、延缓或逆转年龄相关的骨骼肌疾病具有重要的生物医学意义。这项建议的首要目标是研究最近发现的一种骨骼肌健康的全身调节因子--生长分化因子11(GDF11)。虽然GDF11的循环水平在青年时期是丰富的，但由于未知的机制，GDF11的水平随着年龄的增长而大幅下降。大量的初步数据表明，恢复老年小鼠年轻时的GDF11水平大大改善了骨骼肌干细胞(卫星细胞)的功能，并增强了老年肌肉的生理和修复潜力。基于这些发现，我建议检验这一假设，即衰老过程中全身GDF11水平的下降直接导致骨骼肌功能的年龄相关缺陷。为了深入了解GDF11在衰老过程中循环丧失的机制，我将(1)定义产生全身性GDF11的离散细胞类型，并评估它们的数量和GDF11表达水平在衰老过程中的变化。初步研究结果表明，脾是系统性GDF11表达的候选来源，因为GDF11的脾表达在青年时期丰富，并显示出随年龄增长而下降的趋势。一个GDF11报告基因敲入小鼠品系将被利用来通过荧光显微镜和流式细胞术鉴定脾中表达GDF11的细胞类型，并在与年龄相关的GDF11表达下降的背景下评估这些发现。此外，拟议的研究将(2)确定循环中的GDF11在青年时期调节骨骼肌内稳态和修复潜力方面的功能。将使用两种诱导功能丧失的方法来消耗年轻时的GDF11，并分析由此产生的对卫星细胞功能、骨骼肌稳态和体内修复潜力的影响。总之，这些研究将为系统性GDF11在衰老过程中的调节提供机械性的见解，并阐明GDF11作为年轻骨骼肌功能的激素调节器的作用。

 DESCRIPTION (provided by applicant): Skeletal muscle is a highly organized tissue that functions to support bodily movement and locomotion. Throughout adult life, skeletal muscle undergoes a robust process of tissue regeneration in response to injury, yet the effectiveness of this process declines significantly during old age. This age-related skeletal muscle dysfunction poses a significant health concern for the elderly population, such that insufficient muscle repair can lead to decreased muscle mass, loss of strength and impaired quality of life. Thus, the development of novel therapeutics to prevent, delay or reverse age-associated skeletal muscle maladies is of significant biomedical interest. The overarching goal of this proposal is to investigate a recently identified systemic regulator of skeletal muscle health, Growth Differentiation Factor 11 (GDF11). While circulating levels of GDF11 are abundant during youth, GDF11 levels decline substantially with age due to unknown mechanisms. Extensive preliminary data indicate that restoring youthful levels of GDF11 to aged mice substantially improves the function of skeletal muscle stem cells (satellite cells) and enhances the physiology and repair potential of aged muscle. Based on these findings, I propose to test the hypothesis that decreasing systemic GDF11 levels during aging contributes directly to age-related defects in skeletal muscle function. To gain insight into the mechanisms responsible for the loss of GDF11 from circulation during aging, I will (1) define the discrete cell types that produce systemic GDF11 and evaluate changes in their number and GDF11 expression level during aging. Preliminary findings implicate the spleen as a candidate source of systemic GDF11 expression, as splenic expression of GDF11 is abundant during youth and exhibits an age-dependent decline. A knock-in GDF11 reporter mouse strain will be harnessed to identify GDF11-expressing cell types in the spleen by fluorescence microscopy and flow cytometry and evaluate these findings in the context of age-related decreases in GDF11 expression. Additionally, the proposed studies will (2) determine the function of circulating GDF11 in regulating skeletal muscle homeostasis and repair potential during youth. Two inducible loss of function approaches will be used to deplete GDF11 during youth and assay the resulting effects on satellite cell function, skeletal muscle homeostasis and repair potential in vivo. Altogether, these studies will provide mechanistic insights into the regulation of systemic GDF11 during aging and illuminate the role of GDF11 as a hormonal regulator of youthful skeletal muscle function.