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Reduced 40S initiation complex formation in skeletal muscle during sepsis
T C Vary1, C Jurasinski, S R Kimball
1Department of Cellular and Molecular Physiology, Pennsylvania State University, College of Medicine, Hershey 17033, USA.
Molecular and Cellular Biochemistry
|April 18, 1998
Summary
Sepsis severely impairs muscle protein synthesis by hindering the formation of the 40S initiation complex. This study reveals a critical defect in peptide-chain initiation, contributing to muscle wasting during infection.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Sepsis is characterized by severe muscle wasting.
- Previous research indicated sepsis diminishes protein synthesis in fast-twitch muscle fibers.
Purpose of the Study:
- To investigate the specific biochemical reactions causing reduced protein synthesis in sepsis.
- To identify defects in peptide-chain initiation during sepsis.
Main Methods:
- Used gastrocnemius muscles from control and septic rats perfused in situ.
- Analyzed free ribosomal subunits and the incorporation of initiator [35S]methionyl-tRNA (met-tRNA(imet)) into the 40S initiation complex.
- Measured cytoplasmic NADH/NAD+ and NADPH/NADP+ ratios.
Main Results:
- Sepsis impaired peptide-chain initiation, evidenced by a 65% decrease in met-tRNA(imet) binding to the 40S initiation complex.
- The cytoplasmic NADH/NAD+ ratio doubled in septic rats, but this did not explain the impaired complex formation.
- The NADPH/NADP+ ratio remained unchanged.
Conclusions:
- Formation of the 40S initiation complex is a key defect in muscle protein synthesis during sepsis.
- Impaired peptide-chain initiation, not cytoplasmic redox state changes, contributes to muscle wasting in sepsis.