Regulation and function of Growth Differentiation Factor 11 during development and aging

 描述(申请人提供)：健康的骨骼肌对维持正常的身体功能是必不可少的，肌肉在胎儿、新生儿和成年生活中经历了多次发育和功能转变。在生命的最新阶段，肌肉动态平衡受损和肌肉再生潜力降低会导致肌肉质量和力量的进行性丧失。重要的是，老年人的肌肉功能下降是即将死亡的最有力的预测因素之一，这表明，对肌肉衰老的基本机制的更好理解以及对这一过程干预的新策略的开发，将对经历退行性肌肉衰退的日益增长的老年人的寿命和生活质量产生巨大影响。该项目旨在通过关注一种名为生长分化因子11(GDF11，也称为骨形态发生蛋白11，或BMP11)的新型循环激素，增加我们对骨骼肌终生功能的了解。大量已发表的和初步的数据表明，GDF11在调节骨骼肌纤维的动态平衡重塑和肌肉干细胞(卫星细胞)在特定生命阶段的再生活动中发挥关键作用。GDF1蛋白在新生和年轻成年动物(包括人类)中高水平循环，但随着年龄的增长和肌肉和其他组织中多种年龄相关病理的出现，GDF1蛋白急剧下降。我们最近发表的论文数据表明，提高老年小鼠循环中GDF11的水平可以逆转某些与年龄相关的病理变化，包括静息肌肉中卫星细胞数量的恢复和肌肉轻度损伤后肌肉再生能力的恢复。然而，在遭受严重肌肉损伤的年轻小鼠中，这种蛋白的过度产生可能会产生有害的影响。在这个项目中，我们将回答一些问题，以了解这种新的候选衰老肌肉再生因子的调节和活性，以及它在小鼠和人类中调节发育和衰老表型的潜力：(1)确定GDF11终生的细胞来源(S)，并澄清这种激素随年龄下降的基础及其对肌肉修复的潜在年龄和损伤依赖的影响；(2)评估在生命的不同阶段或在离散的GDF11产生细胞中移除GDF11对发育和动态平衡的影响。以及(3)评估人类血清中GDF11丰度和功能的年龄调节变化，并将其与肌肉表现、身体组成和总体身体功能相关联，无论是否有活动能力限制。总之，这些研究将为肌肉发育生物学和衰老提供关键的见解，并可能验证一种有望逆转年龄相关性骨骼肌功能障碍的新候选疗法。

 DESCRIPTION (provided by applicant): Healthy skeletal muscle is essential to sustain normal physical function, and muscle undergoes multiple developmental and functional transitions during fetal, neonatal and adult life. In the latest stages of life, impaired muscle homeostasis and reduced muscle regenerative potential lead to progressive loss of muscle mass and strength. Importantly, reduced muscle function in elderly individuals is one of the strongest predictors of imminent mortality, suggesting that improved understanding of the fundamental mechanisms underlying muscle aging and the development of novel strategies to intervene in this process, would have tremendous impact on lifespan and quality of life of the growing population of aged individuals experiencing degenerative muscle decline. This project is aimed at increasing our understanding of skeletal muscle function throughout life by focusing on a novel circulating hormone called Growth Differentiation Factor 11 (GDF11, also known as Bone Morphogenic Protein 11, or BMP11). Extensive published and preliminary data indicate that GDF11 plays a key role in modulating the homeostatic remodeling of skeletal muscle fibers and the regenerative activity of muscle stem cells (satellite cells) at particular stages of life. GDF1 protein circulates at high levels in neonatal and young adult animals (including humans), but declines dramatically with advancing age and in concert with the emergence of multiple age-associated pathologies in muscle and other tissues. Data from our recently published manuscripts indicate that raising the levels of circulating GDF11 in aged mice can reverse certain age-related pathologies, including recovery of satellite cell numbers in resting muscle and restoration of muscle regenerative potential after mild muscle injury. However, overproduction of this protein in younger mice subjected to severe muscle damage may have a detrimental effect. In this project, we will answer questions crucial to understanding the regulation and activity of this new candidate rejuvenating factor for aged muscle, and its potential for regulating developmental and aging phenotypes in mice and humans by: (1) defining the cellular source(s) of GDF11 throughout life and clarifying the basis for the age-dependent decline of this hormone and its potential age- and injury-dependent effects on muscle repair, (2) evaluating the impact on development and homeostasis of removal of GDF11 at discrete stages of life or in discrete GDF11- producer cells, and (3) assessing age-regulated changes in GDF11 abundance and function in human sera and correlating these with muscle performance, body composition and overall physical function in individuals with or without mobility limitations. Together, these studies will provide critical insights into muscle developmental biology and aging and may validate a promising new candidate therapeutic for the reversal of age-related skeletal muscle dysfunction.