Aging skeletal muscle exhibits a marked decrease in regenerative capabilities, which is associated with fatty infiltration and the deposition of fibrous connective tissue. This fibrotic deposition is particularly harmful because it interferes with proper muscle contraction. 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 PDGF receptor alpha (PDGFR?) signaling promotes proliferation and differentiation of a population of muscle-resident fibroadipogenic progenitors (FAPs), which have been hypothesized to contribute to accumulation of both fibrous connective tissue and fat in muscle with age. Our preliminary data suggest that PDGFR? signaling is upregulated in FAPs upon muscle injury and that changes in this signaling pathway may influence their fibrogenic differentiation potential. We hypothesize that PDGFR? 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 PDGFR? signaling during normal muscle regeneration and testing whether the stimulation and inhibition of the pathway affects the development of fibrosis, and how depletion of FAPs alters muscle regenerative capacity (Aim 1). We will examine how the levels of PDGFR? signaling change in muscle with age and we will investigate whether inhibiting signal transduction results in a reduction in fibrosis accumulation in aged muscle (Aim 2). Finally, we will explore the mechanisms by which the PDGFR? transcript is regulated (Aim 3). Our preliminary data suggest that multiple variants of the PDGFR? transcript are produced that that these variants may alter the ultimate expression of the PDGFR? protein. We will study how PDGFR? is regulated post-transcriptionally through an analysis of polyadenylation site selection. Through our examination of this 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. 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 a therapeutic approach to muscle tissue repair based upon a deep understanding of the basic stem cell biology and a firm commitment to the clinical/translational mission to improve the health and quality of life of Veterans whose function is limited by the lack of effective therapeutic options.

Public Health Relevance

The major focus of our work is to understand the cellular and molecular mechanisms that lead to fibrosis of muscle in the setting of injury, diseases, and aging. Fibrosis is associated with th kind of scarring that leads to changes in muscle that reduces muscle strength and increases muscle stiffness. A population of stem cells known as 'fibroadipogenic progenitors', or 'FAPs', exists within skeletal muscle, and it has been suggested that these cells may be responsible for some or even most of the degenerative changes that occur when muscle regeneration is impaired. The goal of our studies is to understand what mechanisms control the fate and function of these FAPS and to determine the extent to which we can modulate the behavior of these cells in order to reduce the amount of fibrosis that develops in muscle, whether in injury, degenerative diseases, or aging. Our long-term goals are to develop therapies for enhancing muscle regeneration and function in order to improve the health and quality of life of Veterans with muscle injuries and muscle dysfunction.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX002324-03
Application #
8974179
Study Section
Cellular and Molecular Medicine (CAMM)
Project Start
2013-10-01
Project End
2017-09-30
Budget Start
2015-10-01
Budget End
2016-09-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Veterans Admin Palo Alto Health Care Sys
Department
Type
DUNS #
046017455
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Liu, Ling; Charville, Gregory W; Cheung, Tom H et al. (2018) Impaired Notch Signaling Leads to a Decrease in p53 Activity and Mitotic Catastrophe in Aged Muscle Stem Cells. Cell Stem Cell 23:544-556.e4
Filareto, Antonio; Maguire-Nguyen, Katie; Gan, Qiang et al. (2018) Monitoring disease activity noninvasively in the mdx model of Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 115:7741-7746
Tabula Muris Consortium; Overall coordination; Logistical coordination et al. (2018) Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562:367-372
Wosczyna, Michael N; Rando, Thomas A (2018) A Muscle Stem Cell Support Group: Coordinated Cellular Responses in Muscle Regeneration. Dev Cell 46:135-143
Leeman, Dena S; Hebestreit, Katja; Ruetz, Tyson et al. (2018) Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science 359:1277-1283
Judson, Robert N; Quarta, Marco; Oudhoff, Menno J et al. (2018) Inhibition of Methyltransferase Setd7 Allows the In Vitro Expansion of Myogenic Stem Cells with Improved Therapeutic Potential. Cell Stem Cell 22:177-190.e7
Rodgers, Joseph T; Schroeder, Matthew D; Ma, Chanthia et al. (2017) HGFA Is an Injury-Regulated Systemic Factor that Induces the Transition of Stem Cells into GAlert. Cell Rep 19:479-486
van Velthoven, Cindy T J; de Morree, Antoine; Egner, Ingrid M et al. (2017) Transcriptional Profiling of Quiescent Muscle Stem Cells In Vivo. Cell Rep 21:1994-2004
de Morrée, Antoine; van Velthoven, Cindy T J; Gan, Qiang et al. (2017) Staufen1 inhibits MyoD translation to actively maintain muscle stem cell quiescence. Proc Natl Acad Sci U S A 114:E8996-E9005
Luo, Dan; de Morree, Antoine; Boutet, Stephane et al. (2017) Deltex2 represses MyoD expression and inhibits myogenic differentiation by acting as a negative regulator of Jmjd1c. Proc Natl Acad Sci U S A 114:E3071-E3080

Showing the most recent 10 out of 28 publications