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.
This work will investigate a circulating protein (GDF11) that progressively declines during aging and can promote healthy skeletal muscle function when administered to old mice. We will use genetic mouse models to define the sources of GDF11 within the body, determine why the production of GDF11 wanes with increasing age, and evaluate how the premature loss of GDF11 during youth influences skeletal muscle function. Information garnered from this study will inform the development of GDF11-focused therapies to restore healthy muscle function in elderly patients.
| Poggioli, Tommaso; Vujic, Ana; Yang, Peiguo et al. (2016) Circulating Growth Differentiation Factor 11/8 Levels Decline With Age. Circ Res 118:29-37 |
