The determination, differentiation, maturation, and maintenance of skeletal muscle requires ongoing cooperation between signaling pathways activated by hormones and growth factors, and an intrinsic regulatory program controlled by myogenic transcription factors. The insulin-like growth factors (IGFs) play essential roles in normal muscle development in the embryo and are important for coordinating muscle regeneration and re-innervation following neuromuscular injury in the adult. The focus of this application will be on the role of the IGF system in muscle development, and represents part of a long-term effort to understand the mechanisms by which actions of the IGFs, their receptors, and binding proteins are integrated within the cell and in the whole organism. Based on current observations, we have postulated that one key function for the IGFs is to potentiate terminal muscle differentiation by collaborating with myogenic transcription factors. The following four Specific Aims are proposed to test this idea: 1. To define the mechanisms of interaction between myogenic regulatory factors and IGF-mediated signal transduction pathways in muscle differentiation. The major goal will be to test the hypothesis that MyoD and related myogenic regulatory factors initiate an essential amplification cascade involving induced expression of IGF-II, activation of the IGF-I receptor, and stimulation of the PI3-kinase - Akt pathway. 2. To determine the mechanisms of action of Akt in muscle differentiation. Proposed studies will test the idea that Akt is an obligate intermediate in myoblast differentiation, and that one of its major functions is to inhibit the transcriptional co-repressor, N-CoR. 3. To define mechanisms of regulation of IGF-II gene transcription during muscle differentiation. Proposed experiments will test the hypothesis that a critical control region for muscle differentiation-dependent activation of IGF-II gene transcription resides near the HI9 gene. The major goals will be to characterize this chromosomal locus and determine its mechanisms of action. 4. To identify and characterize novel IGF-regulated genes that mediate IGF actions during muscle differentiation. The main goal will be to define the functions of the proteins encoded by five previously unknown genes that are highly induced by IGF signaling early in myoblast differentiation.
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