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.
This work will investigate a novel candidate juvenile protective factor, present at high levels in youth and lost with advancing age, that was identified by our laboratory as a potent stimulator of healthy muscle function. The studies proposed here will define the possible sources of this factor in the body, determine why its levels change with age, and evaluate the impact on muscle function of loss of this factor and restoration of its levels in youth and in old age. Studies will be performed using both mouse and human cells to directly establish the potential therapeutic value of this factor for human patients.
| Bar-Nur, Ori; Gerli, Mattia F M; Di Stefano, Bruno et al. (2018) Direct Reprogramming of Mouse Fibroblasts into Functional Skeletal Muscle Progenitors. Stem Cell Reports 10:1505-1521 |
| Walker, Ryan G; Czepnik, Magdalena; Goebel, Erich J et al. (2017) Structural basis for potency differences between GDF8 and GDF11. BMC Biol 15:19 |
| Walker, Ryan G; Poggioli, Tommaso; Katsimpardi, Lida et al. (2016) Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation. Circ Res 118:1125-41; discussion 1142 |
| Poggioli, Tommaso; Vujic, Ana; Yang, Peiguo et al. (2016) Circulating Growth Differentiation Factor 11/8 Levels Decline With Age. Circ Res 118:29-37 |
| Almada, Albert E; Wagers, Amy J (2016) Molecular circuitry of stem cell fate in skeletal muscle regeneration, ageing and disease. Nat Rev Mol Cell Biol 17:267-79 |
