Redox regulation of diaphragm proteolysis during mechanical ventilation

Abstract

Prevention of oxidative stress via antioxidants attenuates mechanical ventilation (MV) diaphragm myofiber atrophy. The specific redox sensitive mechanisms for this attenuation remain unknown. We hypothesized that skeletal muscle proteolytic activity is a potential site of diaphragm redox regulation during MV. Rats were assigned to: 1) control (Con): 2) 6‐hours of MV (6hr MV); 3) 6‐hours of MV with the antioxidant, Trolox (6hr MVT), 4) 18‐hours of MV (18hr MV); and 5) 18‐hours MV with Trolox (18hr MVT). Trolox did not attenuate MV induced increases in ubiquitin‐protein conjugation, poly‐ubiquitin and proteasomal subunits (20S proteasome α‐subunit 7, 14kDa‐E2, and proteasome‐activating complex PA28) gene expression. However, antioxidant administration reduced both chymotrypsin‐like and PGPH‐like 20‐S proteasome activities. Trolox attenuated MV‐induced increases in the percentage of easily releaseable diaphragm myofilament protein. These data suggest that the protective effect of antioxidant administration on the diaphragm during MV occurs primarily by decreasing myofilament protein substrate availability to the proteasome. This work supported by National Institutes of Health (R01 HL072789).