The mechanisms responsible for the muscle wasting that accompanies chronic alcohol consumption are poorly defined. However, alterations in the bioavailability and bioactivity of insulin-like growth factor (IGF-1), a potent endogenous anabolic hormone which directly regulates muscle proteolysis and synthesis, appears to be a critical causative factor. The long-term goal of the proposed research is to elucidate the mechanisms by which alcohol alters both the hepatic production of IGF-1 and IGF binding protein (BP-1) as well as the responsiveness of skeletal muscle to IGF-1, that in concert contribute to the alcohol-induced myopathy. The proposed research will test three hypotheses: 1) Alcohol alters both basal and hormonal-mediated hepatic synthesis of IGF-1 and IGF BP-1 in a cell-specific manner - this hypothesis will be tested by specific aims to determine alcohol-induced alterations in IGF-1 and IGF BP-1 protein and mRNA abundance, and transcriptional start site usage and rate of transcription for the IGF-1 gene in whole liver and specific hepatic cell types; 2) Chronic alcohol consumption produces a growth hormone (GH) resistance mediated by both receptor and post-receptor defects - this hypothesis will be tested by specific aims to determine GH-responsiveness under in vivo and in situ conditions, as well as by studies designed to determine GH receptor binding characteristics and gene expression in liver and muscle; and 3) Alcohol directly affects the responsiveness of skeletal muscle to IGF-1 resulting in an imbalance between protein synthesis and degradation - this final hypothesis will be addressed by studies to determine a) the ability of IGF-1 to enhance muscle protein synthesis and slow protein degradation in pair-fed control and alcohol-consuming rats b) the components of the IGF-1 signal transduction pathway, and c) how ethanol and IGF binding proteins antagonize the anabolic actions of IGF-1 on muscle protein metabolism under in vitro conditions using L6 myotubes. These studies closely integrate in vivo measurements of the IGF system and protein metabolism with in vitro studies aimed at elucidating cellular mechanisms. The proposed research will provide novel information for the cellular mechanism by which chronic alcohol consumption regulates a key anabolic hormone, IGF-1, and how changes in the IGF system are capable of controlling muscle wasting in patients with alcoholism.
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