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

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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.