Premium
Redox Remodelling in Diaphragm Muscle Adaptation to Chronic Sustained Hypoxia
Author(s) -
O'Halloran Ken,
Sheehan David,
Lewis Philip
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.859.8
Subject(s) - oxidative stress , antioxidant , diaphragm (acoustics) , medicine , endocrinology , chemistry , biochemistry , atrophy , biology , acoustics , physics , loudspeaker
Chronic sustained hypoxia (CH) is a feature of respiratory disease. CH induces functional weakness, atrophy, and mitochondrial remodelling in the diaphragm muscle. We hypothesize that reactive oxygen species are pivotal in diaphragm muscle adaptation to CH. C57BL6/J mice were exposed to CH (FiO 2 =0.1) for one, three, or six weeks. The diaphragm was subsequently profiled using a redox proteomics approach followed by mass spectrometry. Redox‐modified metabolic enzyme activities were assessed. Diaphragm isotonic performance was assessed ex vivo after six weeks of CH ± chronic antioxidant supplementation. Protein carbonyl and free thiol content in the diaphragm were increased and decreased respectively after six weeks of CH – indicative of protein oxidation. CH caused extensive remodelling of proteins key to contractile, metabolic and homeostatic functions. Several oxidative and glycolytic enzyme activities in the diaphragm were decreased by CH. Redox sensitive chymotrypsin‐like proteasome activity of the diaphragm was increased. Atrophy signalling was observed through decreased phospho‐FOXO3a and phospho‐mTOR. HIF‐1α and phospho‐p38 MAPK (but not phospho‐Akt or phospho‐ERK1/2) content was increased in CH diaphragm and this was attenuated by antioxidant treatment. CH exposure decreased force‐ and power‐generating capacity of the diaphragm and this was prevented by antioxidant supplementation with N‐acetyl‐cysteine. Redox remodelling is pivotal for diaphragm adaptation to CH. Atrophy signalling through p38MAPK‐FOXO3a with resultant muscle weakness is a feature of CH. Antioxidant supplementation may be useful as an adjunctive therapy in respiratory‐related diseases characterised by hypoxic stress.