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，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。这个项目的重点是一种新型的终生肌肉健康调节剂。我们大量的初步数据表明，小循环激素生长分化因子11(GDF11，也称为骨形态蛋白11，或BMP11)在调节骨骼肌纤维的动态平衡重塑和肌肉干细胞(也称为卫星细胞)在特定生命阶段的再生活性方面发挥着重要作用。特别是，对GDF11基因敲除小鼠的分析表明，该因子在中轴性骨骼、内分泌和神经系统的正常发育中起着至关重要的作用。虽然GDF11在出生后组织中的作用最近才开始被探索，但它在新生和年轻成年动物中高水平循环，但随着年龄的增长和骨骼肌以及心脏和神经组织中多种年龄相关病理的出现，GDF11蛋白急剧下降。令人兴奋的是，来自我们已发表和提交的手稿的新数据表明，提高老年小鼠循环中GDF11的水平可以显著逆转与年龄相关的病理，包括逆转心肌肥厚、恢复卫星细胞数量和恢复肌肉再生潜力。在这个项目中，我们将回答对于理解这种新激素的调节和活性以及它对调节小鼠和人类发育和衰老表型的潜力至关重要的问题，方法是：(1)确定GDF11在一生中循环的细胞来源(S)，并阐明其随年龄下降的基础；(2)评估在生命的不同阶段移除GDF11对发育和动态平衡的影响；以及(3)评估GDF11在人体组织和血清中的丰度和功能随年龄的调节变化。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，并可能验证逆转与年龄相关的骨骼肌功能障碍的有前途的候选疗法。

DESCRIPTION (provided by applicant): Healthy skeletal muscle is essential to sustain normal physical function, and 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 leads 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 focuses on a novel candidate regulator of muscle health throughout life. Our extensive preliminary data indicate that the small circulating hormone Growth Differentiation Factor 11 (GDF11, also known as Bone Morphogenic Protein 11, or BMP11) plays a profound role in modulating the homeostatic remodeling of skeletal muscle fibers and the regenerative activity of muscle stem cells (also known as satellite cells) at particular stages of life. In particular, analysis of GDF11 knockout mice indicates an essential role for this factor in normal development of the axial skeletal and endocrine and nervous system. Although its role in post-natal tissues has only recently begun to be explored, GDF11 protein circulates at high levels in neonatal and young adult animals, but declines dramatically with advancing age and in concert with the emergence of multiple age-associated pathologies in skeletal muscle, as well as cardiac and neural tissue. Excitingly, new data from our published and submitted manuscripts indicate that raising the levels of circulating GDF11 in aged mice can produce a striking reversal of age-related pathologies, including reversal of cardiac hypertrophy, recovery of satellite cell numbers and restoration of muscle regenerative potential. In this project, we will answer questions crucial to understanding the regulation and activity of this new hormone and its potential for regulating developmental and aging phenotypes in mice and humans by: (1) defining the cellular source(s) of circulating GDF11 throughout life and clarifying the basis for its age-dependent decline, (2) evaluating the impact on development and homeostasis of removal of GDF11 at discrete stages of life, and (3) assessing age-regulated changes in GDF11 abundance and function in human tissue and sera. Together, these studies will provide critical insights into muscle developmental biology and aging and may validate a promising candidate therapeutic for the reversal of age-related skeletal muscle dysfunction.