Combination therapy of insulin-like growth factor (IGF)-I/IGF binding protein (BP)-3 (Iplex, formerly known as Somatokine) is substantially more potent in stimulating skeletal muscle growth than IGF-I therapy alone and prevents its negative side effects, although the mechanisms of IGFBP-3's enhancing effects are not well described. Recent studies suggest that the local production of IGFBP-3 helps mediate IGF-stimulated myoblast differentiation. In fact, IGFBP-3 is produced in differentiating myoblasts, it inhibits myoblast proliferation, localizes to the nucleus and directly binds a subunit of RNA polymerase II (Rpb3) that specifically regulates myoblast differentiation via its interactions with the myogenic transcription factors myogenin and ATF4. IGFBP-3 is also a potent suppressor of some prostate and breast cancers. Thus, its positive effects on skeletal muscle growth may additionally protect against the muscle atrophy and negative nitrogen balance that often occurs in cancer patients while simultaneously stimulating tumor cell apoptosis. A better understanding of IGFBP-3's myogenic role could therefore lead to improved treatments for growth impairments and cancer associated cachexia in addition to muscular dystrophies. The long-term goal of the laboratory is to describe the underlying mechanisms of IGFBP-3-stimulated growth regulation. The immediate goal of these studies is to determine the specific inhibitory mechanisms of IGFBP-3 on myoblast proliferation. The project's specific aims are (1) to determine the structural constraints necessary for IGFBP-3 growth inhibition and (2) to determine whether IGFBP-3 manipulates
