Aging skeletal muscle exhibits a marked decrease in regenerative capabilities, which is associated with fatty infiltration and the deposition of fibrou connective tissue. This fibrotic deposition is particularly harmful because it interferes with propr muscle contraction and limits the effectiveness of gene- and cell-based therapies to restore muscle stem cell function. While this phenomenon has been widely documented, the mechanisms underlying this fibrosis are still under investigation. Unlike aged muscle, young muscle does not develop permanent fibrosis. However, it does display transient collagen deposition after acute injury. An understanding of the molecular pathways that trigger this collagen accumulation in young muscle as well as their dysregulation with age will be important for the development of therapeutics to prevent the progression of this pathology. Several studies have linked fibrosis to increased signaling of the platelet-derived growth factor (PDGF) pathway. Recently, it was shown that PDGFRa signaling promotes proliferation and differentiation of a population of muscle-resident fibroadipogenic progenitors (FAPs), which have been hypothesized to contribute to fat and fibrosis accumulation in muscle with age. Our preliminary data suggest that PDGFRa signaling is upregulated in FAPs upon muscle injury and changes in this signaling pathway may influence their fibrogenic differentiation potential. We hypothesize that PDGFRa signaling in FAPs is responsible for their activation during muscle regeneration and that overstimulation of this pathway causes increased fibrosis. We will examine this hypothesis by studying PDGFRa signaling during normal muscle regeneration and testing whether the stimulation and inhibition of the pathway affects the development of fibrosis (Aim 1). We will also examine how the levels of PDGFRa signaling change in muscle with age and investigate whether inhibiting signal transduction results in a reduction in fibrosis accumulation in aged muscle (Aim 2). We are in the process of generating a unique mouse model that will allow for the tracking of FAP lineage over time and for the manipulation of PDGFRa signaling in an FAP-specific manner. Finally, we will explore the mechanisms by which the PDGFRa transcript is regulated (Aim 3). Previous studies and our preliminary data suggest that multiple variants of the PDGFRa transcript are produced that that these variants may alter the ultimate expression of the PDGFRa protein. We will study how PDGFRa is regulated post-transcriptionally through an analysis of polyadenylation site selection. Through our examination of a newly-discovered population of FAPs, we aim to understand the mechanisms that guide their activation in healthy muscle to assess their role in the fibrotic pathology of aged muscle. Our investigation will both allow for the production of new experimental tools to study this population and lend insight into therapeutic strategies to prevent age-related fibrosis.

Public Health Relevance

Skeletal muscle exhibits an age-associated decline in regenerative potential that is accompanied by a marked deposition of fibrotic tissue, but the mechanisms underlying this fibrosis are still largely unknown. We will investigate the molecular pathways that govern this phenomenon through examination of a newly-discovered stem cell population in muscle. Our studies will lend insight into the development of novel therapeutic strategies to combat these age-related pathologies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F05-R (20))
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Williams, John
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Stanford University
Schools of Medicine
United States
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Du, Hongqing; Shih, Chung-Hsuan; Wosczyna, Michael N et al. (2017) Macrophage-released ADAMTS1 promotes muscle stem cell activation. Nat Commun 8:669
Mueller, Alisa A; van Velthoven, Cindy T; Fukumoto, Kathryn D et al. (2016) Intronic polyadenylation of PDGFR? in resident stem cells attenuates muscle fibrosis. Nature 540:276-279
Mueller, Alisa A; Cheung, Tom H; Rando, Thomas A (2013) All's well that ends well: alternative polyadenylation and its implications for stem cell biology. Curr Opin Cell Biol 25:222-32