Respiratory muscle dysfunction in animal models of hypoxic disease: antioxidant therapy goes from strength to strength

Abstract

The striated muscles of breathing play a critical role in respiratory homeostasis governing blood oxygenation and pH regulation. Upper airway dilator and thoracic pump muscles retain a remarkable capacity for plasticity throughout life, both in health and disease states. Hypoxia, whatever the cause, is a potent driver of respiratory muscle remodeling with evidence of adaptive and maladaptive outcomes for system performance. The pattern, duration, and intensity of hypoxia are key determinants of respiratory muscle structural-, metabolic-, and functional responses and adaptation. Age and sex also influence respiratory muscle tolerance of hypoxia. Redox stress emerges as the principal protagonist driving respiratory muscle malady in rodent models of hypoxic disease. There is a growing body of evidence demonstrating that antioxidant intervention alleviates hypoxia-induced respiratory muscle dysfunction, and that N-acetyl cysteine, approved for use in humans, is highly effective in preventing hypoxia-induced respiratory muscle weakness and fatigue. We posit that oxygen homeostasis is a key driver of respiratory muscle form and function. Hypoxic stress is likely a major contributor to respiratory muscle malaise in diseases of the lungs and respiratory control network. Animal studies provide an evidence base in strong support of the need to explore adjunctive antioxidant therapies for muscle dysfunction in human respiratory disease.

Antioxidant therapy for muscular dystrophy: caveat lector!

“…However, in our view, the cautionary tone espoused in the original article is over‐stated, and distracts from the commendable work of the authors revealing impressive effects of antioxidant intervention in the dystrophin‐deficient mdx mouse model of Duchenne muscular dystrophy. By way of disclosure, our group advocates antioxidant intervention for respiratory muscle dysfunction in respiratory disease, on the basis of observations in several rodent models of hypoxia (reviewed in O'Halloran & Lewis, ). Moreover, we have reported that N ‐acetylcysteine (NAC) is the most effective antioxidant in preventing respiratory muscle weakness and fatigue following exposure to chronic sustained hypoxia (Lewis et al .…”

N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm

“…Oxidative stress is a recognized feature of respiratory disorders including DMD. Targeting oxidative stress within muscle by reducing the bioavailability of ROS or boosting endogenous antioxidant stores are attractive adjunctive therapies, particularly in conditions where redox imbalance presents and contributes to muscle pathology [20,21]. We have previously demonstrated that administration of a superoxide scavenger (Tempol) to mdx mice for two weeks restores metabolic enzyme activities and improves diaphragm muscle force-generating capacity [22].…”

Diaphragm fatigue: Similarities and differences between sexes

“…Acute exposure to hypoxia can enhance diaphragm fatigue. There are reports of greater hypoxic tolerance in respiratory muscles of female rodents, purportedly as a result of the protective effects of oestrogen, particularly relevant to chronic exposure to hypoxia in the context of disease (O'Halloran & Lewis, 2017). In this issue of The Journal of Physiology , Archiza et al .…”

“…The hypoxic tolerance in men is curious given that a substantial enhancement of male diaphragm fatigue during hypoxia has been reported elsewhere (Verges et al . 2010). The difference may relate to temporal responses in acute hypoxia because Verges et al .…”

“…The difference may relate to temporal responses in acute hypoxia because Verges et al . (2010) used isocapnic hyperpnoea tests at 85% of maximum voluntary ventilation lasting 15 minutes. Indeed, during hypoxia, a linear decline in transdiaphragmatic twitch pressure has been described (Walker et al .…”