Skeletal muscle tissue is repaired and maintained for the lifetime of mammalian organisms but can be compromised by diseases and in aged individuals. The adult stem cell responsible for regenerating and main- taining skeletal muscle tissue is the rare satellite cell, comprising 2-4% of the total muscle nuclei. The satellite cell is named for its anatomical localization in skeletal muscle tissue, where these cells are typically quiescent and lie sandwiched between the plasma membrane of the myofiber and the basement membrane. When in- jured, the quiescent satellite cell responds by sequentially ?activating,? entering the cell cycle, proliferating as progenitors and then undergoing terminal differentiation and fusion to repair damaged myofibers or fusion with each other to form new myofibers. A small number of satellite cells self-renew, re-acquiring a quiescent state and re-occupying the satellite cell niche to provide continuous maintenance and repair. The severity of a muscle injury recruits satellite cells, which expand to repair the damage and then, return to pre-injury numbers once regeneration is completed. What signals are responsible for terminating satellite cell expansion during regeneration? When do satellite cells self-renew in vivo? How does the ?severity? of a muscle injury recruit sat- ellite cells? What mechanisms ensure that satellite cells are re-established at pre-injury numbers once regener- ation is complete? We have identified a cell-cell interaction between satellite cells and invading cells appearing between 4 days and 7 days following a muscle injury that appears to regulate satellite cell numbers. The num- bers of invading cells directly correlate with the severity of a muscle injury and thus, may regulate satellite cell numbers commensurate with injury severity. We posit that a cell non-autonomous response to a muscle injury conveys the extent of muscle damage directly to the expanding satellite cells, enabling the stem cells to appro- priately respond and ensuring the appropriate numbers of progenitors are available for repair and for self-re- newal to repopulate the stem cell pool. If confirmed, the cell non-autonomous regulation of the skeletal muscle stem cell pool represents a new paradigm for conveying the extent of tissue damage to a resident stem cell and will identify new therapeutic targets to manipulate satellite cell number and potentially improve cell transplan- tation as well as muscle regeneration.

Public Health Relevance

Skeletal muscle is essential for respiration, locomotion, elimination of waste; severe loss of skeletal muscle during aging is catastrophic, shortening lifespan and dramatically reducing overall quality of life. We propose to elucidate the molecular mechanisms regulating homeostasis of skeletal muscle stem cells and inves- tigate the consequences of manipulating muscle stem cell numbers on skeletal muscle function. A better under- standing of the mechanisms regulating muscle stem cell function will permit the development of therapies to target the loss of muscle stem cells in aged muscle and to better understand muscle stem cell exhaustion and dysfunction in patients with skeletal muscle diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049446-15
Application #
9966715
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Boyce, Amanda T
Project Start
2005-04-01
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
15
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80303
Pawlikowski, Bradley; Vogler, Thomas Orion; Gadek, Katherine et al. (2017) Regulation of skeletal muscle stem cells by fibroblast growth factors. Dev Dyn 246:359-367
Hall, Monica N; Hall, John K; Cadwallader, Adam B et al. (2017) Transplantation of Skeletal Muscle Stem Cells. Methods Mol Biol 1556:237-244
Harper, Shavonn C; Brack, Andrew; MacDonnell, Scott et al. (2016) Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects? Circ Res 118:1143-50; discussion 1150
Pisconti, Addolorata; Banks, Glen B; Babaeijandaghi, Farshad et al. (2016) Loss of niche-satellite cell interactions in syndecan-3 null mice alters muscle progenitor cell homeostasis improving muscle regeneration. Skelet Muscle 6:34
Chenette, Devon M; Cadwallader, Adam B; Antwine, Tiffany L et al. (2016) Targeted mRNA Decay by RNA Binding Protein AUF1 Regulates Adult Muscle Stem Cell Fate, Promoting Skeletal Muscle Integrity. Cell Rep 16:1379-1390
Pawlikowski, Bradley; Pulliam, Crystal; Betta, Nicole Dalla et al. (2015) Pervasive satellite cell contribution to uninjured adult muscle fibers. Skelet Muscle 5:42
Bustos, Francisco; de la Vega, Eduardo; Cabezas, Felipe et al. (2015) NEDD4 Regulates PAX7 Levels Promoting Activation of the Differentiation Program in Skeletal Muscle Precursors. Stem Cells 33:3138-51
Doles, Jason D; Olwin, Bradley B (2015) Muscle stem cells on the edge. Curr Opin Genet Dev 34:24-8
Hausburg, Melissa A; Doles, Jason D; Clement, Sandra L et al. (2015) Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay. Elife 4:e03390
Bernet, Jennifer D; Doles, Jason D; Hall, John K et al. (2014) p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat Med 20:265-71

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