REGULATION OF SKELETAL MUSCLE METABOLISM

Project: Research project

Project Details

Description

Disorders of protein metabolism in skeletal muscle are central to
the pathogenesis of diabetes and other disease states that affect
nutrient homeostasis. Development of rational approaches to
treatment of these disorders requires knowledge of the basic
events involved in the regulation of protein metabolism.
Therefore, the overall goal of the project is to provide a better
understanding of the mechanisms by which insulin regulates
specific events in the protein synthetic pathway in skeletal
muscle. Studies proposed for the next project period are designed
to elucidate the mechanism of insulin action on the first event in
the translational phase of protein synthesis, i.e., formation of a
43S initiation complex composed of eukaryotic initiation factor
eIF-2, GTP, initiator methionyl-tRNA, and a 40S ribosomal
subunit. Additionally, they are designed to provide new insights
into a role for insulin in the regulation of pretranslational events
in skeletal muscle. The specific aims of the studies are: (1) to
further characterize effect of insulin on eIF-2, particularly with
respect to covalent modifications, intracellular distribution, and
interaction with the guanine nucleotide exchange factor (GEF); (2)
to establish and characterize muscle cell cultures in which insulin
regulates peptide-chain initiation and from which can be prepared
an active cell-free, protein-synthesizing system; (3) to investigate
effects of insulin on activity and content of eIF-2 and GEF, and
relate their content to number of ribosomes and rate of protein
synthesis; (4) to clone cdna sequences coding for the alpha- and
beta-subunits of eIF-2, to derive the amino acid structure of the
subunits from sequence analysis of the cDNA inserts, and to
employ the cDNA clones to quantitate the amount of mRNA for
the alpha- and beta-subunits; and (5) to investigate effects of
insulin on total and selected mRNA species, and to clone cDNA
sequences coding for proteins that show large and rapid responses
to insulin. The studies are to utilize a number of methodologies
including muscle perfusion, cell culture, cell-free protein-
synthesizing systems, protein purification, immunochemical
identification and quantitation of proteins, one- and two-
dimensional gel electrophoresis, and quantitation of mRNA using
specific cDNAs. Overall, the studies described in this proposal
should help identify mechanisms by which insulin regulates protein
synthesis in skeletal muscle. They should also provide new
insights into biochemical events involved in peptide-chain
initiation.
StatusActive
Effective start/end date12/31/894/30/21

Funding

  • NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES: $383,375.00
  • NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES: $383,204.00
  • NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES: $382,844.00
  • NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES: $383,027.00

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