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Hypoxic Preconditioning Improves Respiratory Muscle Function during Hypoxia by Regulating Mitochondria in COPD Mice
Author(s) -
Zuo Li,
Chuang ChiaChen,
Zhou Tingyang
Publication year - 2017
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.31.1_supplement.841.2
Subject(s) - copd , mitochondrial permeability transition pore , glibenclamide , mptp , hypoxia (environmental) , chemistry , mitochondrion , respiratory system , potassium channel , medicine , diazoxide , diaphragm (acoustics) , endocrinology , pharmacology , anesthesia , cardiology , biochemistry , disease , insulin , oxygen , diabetes mellitus , organic chemistry , apoptosis , physics , programmed cell death , parkinson's disease , loudspeaker , acoustics
Diaphragm weakness has been observed in patients with chronic obstructive pulmonary disease (COPD), which may be associated with the prolonged hypoxic conditions in the disease. We found that hypoxic preconditioning (HPC) can strengthen diaphragm under hypoxic conditions in COPD mice by treating the muscle with alternating low and high O 2 concentrations. In this study, we tested the hypothesis that the protective effects offered by HPC are linked with the opening of mitochondrial ATP‐sensitive potassium channel (K ATP ) and the closing of the mitochondrial permeability transition pore (mPTP) in COPD mice. Adult C57BL6 mice were smoked for three months to develop COPD symptoms. Following the completion of smoking, diaphragms of the mice were isolated and mounted in a contractile chamber. Each muscle strip was treated (n = 6) or non‐treated with HPC (n = 6), or pre‐incubated with a combination of K ATP channel inhibitor (glibenclamide; 100 μM) and mPTP opener (carboxyatractyloside; 50 μM; n = 6) for 30 min prior to HPC. Another two groups of muscles were treated either with K ATP channel activator (diazoxide; 100 μM; n = 6) or mPTP inhibitor (cyclosporine A; 100 μM; n = 6) in the absence of HPC. The muscles were then consecutively stimulated for five minutes (0.5 Hz) during a 30‐min hypoxic period. Fatigue tolerance was determined as the ratio of residual force at the end of the five‐min contraction to the initial force. Data were expressed as means ± SE, and analyzed using multi‐way ANOVA. P < 0.05 was considered statistically different. Our results show that HPC significantly improved diaphragm function during hypoxia (29 ± 2.8% for HPC vs. 6 ± 1.3% for control, p < 0.05). However, such protective effects were eliminated via the simultaneous inhibition of K ATP channel and the opening of mPTP (5 ± 2.1%, p < 0.05 vs. HPC). On the other hand, either the activation of K ATP channel (27 ± 2.6%) or the inhibition of mPTP (24 ± 3.6%) significantly mitigates diaphragm fatigue ( p < 0.05 vs. control) to an extent similar to that of HPC. These data collectively indicate that the mechanisms of HPC protection on diaphragm under hypoxia may involve the opening of mitochondrial K ATP channel and inhibition of mPTP in COPD mice. Support or Funding Information American Physiological Society (APS) 2016 S&R Foundation Ryuji Ueno Award