Skeletal muscle is terminally differentiated and as such, cannot regenerate. The cells responsible for muscle regeneration are known as satellite cells, which are normally quiescent and reside between the basement membrane and the sarcolemma of the muscle fiber. Because these cells comprise only 1-6% of the total number of muscle nuclei, little specific information is known regarding the mechanisms that regulate satellite cell function. We have recently identified two satellite cell surface receptors, syndecan-3 and syndecan-4, which are two related members of a family of 4 heparan sulfate proteoglycans that are critical regulators of satellite cell function. These proteins are comprised of a core type I integral membrane protein whose extracellular domain is decorated with heparan sulfate glycosaminoglycan (GAG) chains. Both syndecan-3 and syndecan-4 are functionally critical for satellite cells as is evident from the phenotypes of syndecan-3-/- and syndecan-4-/- mice. Satellite cells from syndecan-4 nulls appear to be generally incapable of activation and proliferation. They fail to express MyoD, myogenin and myosin heavy chain (MyHC), yet these mice appear generally normal at birth. Consistent with a satellite cell defect, muscle regeneration in these mice is severely impaired. Syndecan-3-/- mice display a strikingly different phenotype, having a large excess of myonuclei and satellite cells. Muscle sections reveal fatty and connective tissue infiltrates as well as nascent myofibers containing centrally located nuclei. It is noteworthy that null alleles for these two related and co-expressed HSPGs exhibit remarkably distinct phenotypes and appear to regulate distinct aspects of satellite cell physiology. We propose to: (i) identify the onset of the skeletal muscle phenotypes in syndecan-3-/- and syndecan-4-/- mice; (ii) functionally characterize the roles syndecan-3 and syndecan-4 play in skeletal muscle regeneration; and, (iii) identify molecular differences between wt, syndecan-3-/- and syndecan-4-/- satellite cells contributing to the observed phenotypes. These studies will provide new insights and add significant knowledge to our understanding of the regulation of muscle regeneration regulated by interactions between the satellite cell extracellular matrix and intracellular signal transduction pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049446-03
Application #
7216331
Study Section
Development - 1 Study Section (DEV)
Program Officer
Boyce, Amanda T
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$306,413
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
80309
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

Showing the most recent 10 out of 20 publications