Redox regulation of diaphragm proteolysis during mechanical ventilation

J. M. McClung, M. A. Whidden, A. N. Kavazis, D. J. Falk, K. C. DeRuisseau, S. K. Powers

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Prevention of oxidative stress via antioxidants attenuates diaphragm myofiber atrophy associated with mechanical ventilation (MV). However, the specific redox-sensitive mechanisms responsible for this remain unknown. We tested the hypothesis that regulation of skeletal muscle proteolytic activity is a critical site of redox action during MV. Sprague-Dawley rats were assigned to five experimental groups: 1) control, 2) 6 h of MV, 3) 6 h of MV with infusion of the antioxidant Trolox, 4) 18 h of MV, and 5) 18 h of MV with Trolox. Trolox did not attenuate MV-induced increases in diaphragmatic levels of ubiquitin-protein conjugation, polyubiquitin mRNA, and gene expression of proteasomal subunits (20S proteasome α-subunit 7, 14-kDa E2, and proteasome-activating complex PA28). However, Trolox reduced both chymotrypsin-like and peptidylglutamyl peptide hydrolyzing (PGPH)-like 20S proteasome activities in the diaphragm after 18 h of MV. In addition, Trolox rescued diaphragm myofilament protein concentration (μg/mg muscle) and the percentage of easily releasable myofilament protein independent of alterations in ribosomal capacity for protein synthesis. In summary, these data are consistent with the notion that the protective effect of antioxidants on the diaphragm during MV is due, at least in part, to decreasing myofilament protein substrate availability to the proteasome.

Original languageEnglish (US)
Pages (from-to)R1608-R1617
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume294
Issue number5
DOIs
StatePublished - May 1 2008
Externally publishedYes

Keywords

  • Atrophy
  • Protein synthesis
  • Redox balance

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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