Aging, severe injury and skeletal muscle diseases all result in the loss of skeletal muscle tissue. Although skeletal muscle has a large regenerative capacity, a permanent loss of skeletal muscle tissue can occur in each of these clinical occurrences. The molecular mechanisms that regulate skeletal muscle regeneration are largely unknown. Implicated in skeletal muscle growth and regeneration are extracellular factors that include the insulin-like growth factors (IGFs), the fibroblast growth factor (FGFs), the transforming growth factor family (TGFs and GDFs), and hepatocyte growth factor (HGF). The loss of skeletal muscle function occurring in humans with muscular dystrophy and aging has been attributed to a loss of muscle regenerative capacity, but little is known concerning the mechanisms involved in this process. Myoblast transfer therapy to alleviate these symptoms is largely unsuccessful in animals and humans due to the death of greater than or equal to 95 percent of myoblasts following injection and the poor proliferative potential of the remaining cells. As an alternative, gene therapy with adenoviruses may be difficult due to the large mass of muscle tissue. It is likely that a combination of these procedures will be required to eventually cure muscle diseases and recover muscle tissue in patients exhibiting severe cachexia. In order to make myoblast transfer therapy successful, it will be necessary to manipulate the decision of a committed myoblast to proliferate, remain quiescent and undifferentiated, or to terminally differentiate and undergo cell fusion. A primary goal of the proposed research is to understand the relationships that regulate proliferation and differentiation in myogenic cells.
The specific aims are to: 1. characterize the molecular mechanisms that are utilized by intracellular FGF-2 to promote myoblast proliferation; 2. analyze potential MAPK phosphatase 1 (MKP1) substrates and determine their involvement in FGF-mediated repression of skeletal muscle differentiation; 3. identify unknown MKP1 substrates that may act to mediate repression of differentiation by FGFs; 4. characterize MKP1 substrates identified in aim 3 and determine their involvement in repression of skeletal muscle differentiation. These goals will be accomplished by a combination of approaches that include the use of novel FGF-2 fusion proteins that partition into the cytoplasm via a receptor-independent mechanism, expression of mutant signal transducers, identification of unknown substrates by nanospray mass spectrometry, and determination that the identified MKP1 substrates are clinical regulators of skeletal muscle differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR039467-12
Application #
2911337
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Lymn, Richard W
Project Start
1999-07-15
Project End
2004-06-30
Budget Start
1999-07-15
Budget End
2000-06-30
Support Year
12
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309
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
Farina, Nicholas H; Hausburg, Melissa; Betta, Nicole Dalla et al. (2012) A role for RNA post-transcriptional regulation in satellite cell activation. Skelet Muscle 2:21
Doyle, Michelle J; Zhou, Sheng; Tanaka, Kathleen Kelly et al. (2011) Abcg2 labels multiple cell types in skeletal muscle and participates in muscle regeneration. J Cell Biol 195:147-63
OlguĂ­n, Hugo C; Patzlaff, Natalie E; Olwin, Bradley B (2011) Pax7-FKHR transcriptional activity is enhanced by transcriptionally repressed MyoD. J Cell Biochem 112:1410-7
Bren-Mattison, Yvette; Hausburg, Melissa; Olwin, Bradley B (2011) Growth of limb muscle is dependent on skeletal-derived Indian hedgehog. Dev Biol 356:486-95
Shi, Hao; Boadu, Emmanuel; Mercan, Fatih et al. (2010) MAP kinase phosphatase-1 deficiency impairs skeletal muscle regeneration and exacerbates muscular dystrophy. FASEB J 24:2985-97
Hall, John K; Banks, Glen B; Chamberlain, Jeffrey S et al. (2010) Prevention of muscle aging by myofiber-associated satellite cell transplantation. Sci Transl Med 2:57ra83
Pisconti, Addolorata; Cornelison, D D W; Olguin, Hugo C et al. (2010) Syndecan-3 and Notch cooperate in regulating adult myogenesis. J Cell Biol 190:427-41
Tanaka, Kathleen Kelly; Hall, John K; Troy, Andrew A et al. (2009) Syndecan-4-expressing muscle progenitor cells in the SP engraft as satellite cells during muscle regeneration. Cell Stem Cell 4:217-25
Jones, Nathan C; Tyner, Kristina J; Nibarger, Lisa et al. (2005) The p38alpha/beta MAPK functions as a molecular switch to activate the quiescent satellite cell. J Cell Biol 169:105-16

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