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.
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