Chronic Intermittent Hypoxia-Induced Diaphragm Muscle Weakness Is NADPH Oxidase-2 Dependent

Chronic intermittent hypoxia (CIH)-induced redox alterations underlie diaphragm muscle dysfunction. We sought to establish if NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS) underpin CIH-induced changes in diaphragm muscle, which manifest as impaired muscle performance. Adult male mice (C57BL/6J) were assigned to one of three groups: normoxic controls (sham); chronic intermittent hypoxia-exposed (CIH, 12 cycles/hour, 8 h/day for 14 days); and CIH + apocynin (NOX2 inhibitor, 2 mM) administered in the drinking water throughout exposure to CIH. In separate studies, we examined sham and CIH-exposed NOX2-null mice (B6.129S-Cybb(TM1Din)(/J)). Apocynin co-treatment or NOX2 deletion proved efficacious in entirely preventing diaphragm muscle dysfunction following exposure to CIH. Exposure to CIH had no effect on NOX2 expression. However, NOX4 mRNA expression was increased following exposure to CIH in wild-type and NOX2 null mice. There was no evidence of overt CIH-induced oxidative stress. A NOX2-dependent increase in genes related to muscle regeneration, antioxidant capacity, and autophagy and atrophy was evident following exposure to CIH. We suggest that NOX-dependent CIH-induced diaphragm muscle weakness has the potential to affect ventilatory and non-ventilatory performance of the respiratory system. Therapeutic strategies employing NOX2 blockade may function as an adjunct therapy to improve diaphragm muscle performance and reduce disease burden in diseases characterised by exposure to CIH, such as obstructive sleep apnoea.

Automated summary

Chronic intermittent hypoxia-induced redox alterations cause diaphragm muscle dysfunction. NADPH oxidase 2-derived reactive oxygen species are involved in these changes, leading to impaired muscle performance. Blocking NOX2 or deleting NOX2 effectively prevents diaphragm muscle dysfunction caused by chronic intermittent hypoxia. NOX2 inhibition does not affect NOX2 expression, but increases NOX4 mRNA expression. NOX-dependent changes in genes related to muscle regeneration, antioxidant capacity, and autophagy and atrophy are observed in response to chronic intermittent hypoxia. Therapeutic strategies targeting NOX2 may improve diaphragm muscle performance and reduce disease burden in conditions characterized by chronic intermittent hypoxia exposure.