Diaphragm muscle weakness and increased UCP-3 gene expression following acute hypoxic stress in the mouse

•Acute sustained hypoxic stress is sufficient to cause diaphragm muscle weakness.•Functional changes may relate to mitochondrial function and/or SR Ca2+ release.•There was no persistent change in ventilation (diaphragm muscle activity).•Muscle weakness and mRNA changes are likely due to direct effects of hypoxia.•Hypoxia may influence diaphragm weakness in acute respiratory-related disorders.

The effects of acute hypoxia on the diaphragm are largely unknown despite the clinical relevance to respiratory conditions such as acute respiratory distress syndrome and ventilator-induced lung injury.Adult male C57BL6/J mice were exposed to 1, 4 or 8 h of hypoxia (FiO2 = 0.10) or normoxia. Ventilation was assessed by whole-body plethysmography during gas exposures. Diaphragm isotonic contractile parameters were assessed ex vivo. Diaphragm gene expression was determined using qRT-PCR.Acute hypoxic stress resulted in significant diaphragm muscle weakness. Gene expression data revealed that hypoxia results in temporal changes in various transcriptional genes regulating mitochondrial function and a time-dependent progressive increase in the expression of the mitochondrial uncoupling protein 3 (UCP-3) with concomitant changes in genes encoding sarcoplasmic reticulum calcium release proteins.Altered gene expression and muscle weakness are likely due to direct effects of hypoxic stress per se, and not related to increased diaphragm muscle activity, as there was no persistent change in ventilation during hypoxic exposure. These findings suggest a potentially critical role for hypoxia in diaphragm muscle remodeling in acute respiratory-related disorders.