REGULATION OF IGF SYSTEM AND MUSCLE WASTING BY ALCOHOL

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from the Investigator's Abstract): 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.
StatusFinished
Effective start/end date5/1/973/31/07

Funding

  • National Institute on Alcohol Abuse and Alcoholism: $280,282.00
  • National Institute on Alcohol Abuse and Alcoholism
  • National Institute on Alcohol Abuse and Alcoholism: $280,303.00
  • National Institute on Alcohol Abuse and Alcoholism: $255,942.00
  • National Institute on Alcohol Abuse and Alcoholism: $280,261.00
  • National Institute on Alcohol Abuse and Alcoholism: $273,631.00
  • National Institute on Alcohol Abuse and Alcoholism: $280,239.00
  • National Institute on Alcohol Abuse and Alcoholism: $263,621.00
  • National Institute on Alcohol Abuse and Alcoholism

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