Hypoxic Preconditioning Attenuates Reoxygenation-Induced Skeletal Muscle Dysfunction in Aged Pulmonary TNF-α Overexpressing Mice

Abstract

Aim: Skeletal muscle subjected to hypoxia followed by reoxygenation is susceptible to injury and subsequent muscle function decline. This phenomenon can be observed in the diaphragm during strenuous exercise or in pulmonary diseases such as chronic obstructive pulmonary diseases (COPD). Previous studies have shown that PO2 cycling or hypoxic preconditioning (HPC), as it can also be referred to as, protects muscle function via mechanisms involving reactive oxygen species (ROS). However, this HPC protection has not been fully elucidated in aged pulmonary TNF-α overexpressing (Tg+) mice (a COPD-like model). We hypothesize that HPC can exert protection on the diaphragms of Tg+ mice during reoxygenation through pathways involving ROS/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/extracellular signal regulated kinase (ERK), as well as the downstream activation of mitochondrial ATP-sensitive potassium channel (mitoKATP) and inhibition of mitochondrial permeability transition pore (mPTP).Methods: Isolated Tg+ diaphragm muscle strips were pre-treated with inhibitors for ROS, PI3K, Akt, ERK, or a combination of mitoKATP inhibitor and mPTP opener, respectively, prior to HPC. Another two groups of muscles were treated with either mitoKATP activator or mPTP inhibitor without HPC. Muscles were treated with 30-min hypoxia, followed by 15-min reoxygenation. Data were analyzed by multi-way ANOVA and expressed as means ± SE.Results: Muscle treated with HPC showed improved muscle function during reoxygenation (n = 5, p < 0.01). Inhibition of ROS, PI3K, Akt, or ERK abolished the protective effect of HPC. Simultaneous inhibition of mitoKATP and activation of mPTP also diminished HPC effects. By contrast, either the opening of mitoKATP channel or the closure of mPTP provided a similar protective effect to HPC by alleviating muscle function decline, suggesting that mitochondria play a role in HPC initiation (n = 5; p < 0.05).Conclusion: Hypoxic preconditioning may protect respiratory skeletal muscle function in Tg+ mice during reoxygenation through redox-sensitive signaling cascades and regulations of mitochondrial channels.