Regulation of Muscle Fibrosis in Response to Injury and Aging
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Fibrotic and adipogenic infiltration is a hallmark of injured and aged skeletal muscle. This muscle fibroadipogenic degeneration (or “MFD”) is responsible in part for the functional decline of skeletal muscle and the increased prevalence of metabolic disorders in aged individuals. The origins of the major cellular contributors (fibrocytes and adipocytes) of this MFD remain to be identified. Fibroadipogenic progenitors (“FAPs”), mesenchymal stem cells that reside in the muscle interstitium, are a leading candidate as they display robust fibrogenic and adipogenic potential in vitro and in vivo following transplantation. However, FAPs as undifferentiated progenitors are believed to have a positive influence on muscle regeneration and homeostasis. Thus, FAPs have been hypothesized to have either a positive or negative influence on muscle depending on their state. Studies in vivo to directly test these dual effects have been limited by the lack of specific tools to genetically label and target FAPs, and this has impaired our understanding of the biology of FAPs in their endogenous milieu. We have recently developed such tools by taking advantage of the highly specific expression of PDGFRα in FAPs among the mononucleated cells of muscle. Our Preliminary Data using a PDGFRαCreER strain that we developed to either genetically label or specifically deplete FAPs support the hypothesis that FAPs are essential for normal muscle regeneration (positive effect) and contribute to MFD under pathologic conditions (negative effect). In the studies of this proposal, we will explore the biology of FAPS along several directions. In Aim 1, we will examine the contribution of FAPs to the cellular components of MFD during aging or during pathologic regeneration using genetic lineage tracing and genetic depletion. In the studies of Aim 2, we will focus on testing the positive role of FAPs in normal muscle regeneration and how changes that occur in FAPs with age may both contribute to age-related decline in muscle regenerative potential and also to age-related changes in muscle homeostasis. In the studies of Aim 3, we will examine the regulation of FAP fate determination, specifically focusing on the role of miRNAs as determinants of lineage based up on our Preliminary Data. We will screen for miRNAs that are important for driving FAPs down particular lineages or for maintaining those differentiated states, and we will test for the ability of specific miRNAs to maintain FAPs in their undifferentiated, progenitor state. Through our studies of FAPs, we aim to understand the mechanisms that guide their activation in healthy muscle to assess their role in the fibroadipogenic pathology of aged muscle. Our investigation will both capitalize on new experimental tools to study this population and lend insight into therapeutic strategies to prevent age-related MFD. This will have direct relevance to Veterans who are suffering from skeletal muscle injuries, injuries that have limited their functional capacity and that, to date, have no hope of further recovery. This will also be directly relevant to our aging Veteran population, many of whom experience decreasing muscle strength and increasing muscle stiffness, limiting their normal activities. Our goal is to develop therapeutic approaches to enhance muscle repair and prevent muscle degeneration based upon a thorough understanding of the basic stem cell biology. These goals are based upon a firm commitment to a mission to improve the health and quality of life of Veterans whose function is limited by the lack of effective therapeutic options.
