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Duchenne muscular dystrophy (DMD) is characterised by respiratory muscle injury, inflammation, fibrosis and weakness, ultimately culminating in respiratory failure. The dystrophin‐deficient mouse model of DMD (mdx) shows evidence of respiratory muscle remodelling and dysfunction contributing to impaired respiratory system performance. The antioxidant N‐acetylcysteine (NAC) has been shown to exert anti‐inflammatory and anti‐fibrotic effects leading to improved respiratory muscle performance in a range of animal models of muscle dysfunction, including mdx mice, following short‐term administration (2 weeks). We sought to build on previous work by exploring the effects of chronic NAC administration (3 months) on respiratory system performance in mdx mice. One‐month‐old male mdx mice were randomised to receive normal drinking water (n = 30) or 1% NAC in the drinking water (n = 30) for 3 months. At 4 months of age, we assessed breathing in conscious mice by plethysmography followed by ex vivo assessment of diaphragm force‐generating capacity. Additionally, diaphragm histology was performed. In separate studies, in anaesthetised mice, respiratory electromyogram (EMG) activity and inspiratory pressure across a range of behaviours were determined, including assessment of peak inspiratory pressure‐generating capacity. NAC treatment did not affect force‐generating capacity of the mdx diaphragm. Collagen content and immune cell infiltration were unchanged in mdx + NAC compared with mdx diaphragms. Additionally, there was no significant effect of NAC on breathing, ventilatory responsiveness, inspiratory EMG activity or inspiratory pressure across the range of behaviours from basal conditions to peak system performance. We conclude that chronic NAC treatment has no apparent beneficial effects on respiratory system performance in the mdx mouse model of DMD suggesting limited potential of NAC treatment alone for human DMD. What is the central question of this study?Does chronic treatment with the antioxidant, anti‐inflammatory and anti‐fibrotic dietary supplement N‐acetyl cysteine (NAC) improve respiratory system performance in the mdx mouse model of Duchenne muscular dystrophy?What is the main finding and its importance?Chronic treatment with NAC does not improve a range of respiratory‐related parameters in mdx mice suggesting limited potential for NAC alone as an intervention in Duchenne muscular dystrophy. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disease. Lack of dystrophin in skeletal muscles leads to intrinsic weakness, injury, subsequent degeneration and fibrosis, decreasing contractile function. Dystropathology eventually presents in all inspiratory and expiratory muscles of breathing, severely curtailing their critical function. In people with DMD, premature death is caused by respiratory or cardiac failure. There is an urgent need to develop therapies that improve quality of life and extend life expectancy in DMD. Surprisingly, there is a dearth of information on respiratory control in animal models of DMD, and respiratory outcome measures are often limited or absent in clinical trials. Characterization of respiratory performance in murine and canine models has revealed extensive remodelling of the diaphragm, the major muscle of inspiration. However, significant compensation by extradiaphragmatic muscles of breathing is evident in early disease, contributing to preservation of peak respiratory system performance. Loss of compensation afforded by accessory muscles in advanced disease is ultimately associated with compromised respiratory performance. A new and potentially more translatable murine model of DMD, the D2.mdx mouse, has recently been developed. Respiratory performance in D2.mdx mice is yet to be characterized fully. However, based on histopathological features, D2.mdx mice might serve as useful preclinical models, facilitating the testing of new therapeutics that rescue respiratory function. This review summarizes the pathophysiological mechanisms associated with DMD both in humans and in animal models, with a focus on breathing. We consider the translational value of each model to human DMD and highlight the urgent need for comprehensive characterization of breathing in representative preclinical models to better inform human trials. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH) is the dominant pathological feature of human obstructive sleep apnoea (OSA), which is highly prevalent and associated with cardiovascular and renal diseases. CIH causes hypertension, centred on sympathetic nervous overactivity, which persists following removal of the CIH stimulus. Molecular mechanisms contributing to CIH‐induced hypertension have been carefully delineated. However, there is a dearth of knowledge on the efficacy of interventions to ameliorate high blood pressure in established disease. CIH causes endothelial dysfunction, aberrant structural remodelling of vessels and accelerates atherosclerotic processes. Pro‐inflammatory and pro‐oxidant pathways converge on disrupted nitric oxide signalling driving vascular dysfunction. In addition, CIH has adverse effects on the myocardium, manifesting atrial fibrillation, and cardiac remodelling progressing to contractile dysfunction. Sympatho‐vagal imbalance, oxidative stress, inflammation, dysregulated HIF‐1α transcriptional responses and resultant pro‐apoptotic ER stress, calcium dysregulation, and mitochondrial dysfunction conspire to drive myocardial injury and failure. CIH elaborates direct and indirect effects in the kidney that initially contribute to the development of hypertension and later to chronic kidney disease. CIH‐induced morphological damage of the kidney is dependent on TLR4/NF‐κB/NLRP3/caspase‐1 inflammasome activation and associated pyroptosis. Emerging potential therapies related to the gut–kidney axis and blockade of aryl hydrocarbon receptors (AhR) are promising. Cardiorenal outcomes in response to intermittent hypoxia present along a continuum from adaptation to maladaptation and are dependent on the intensity and duration of exposure to intermittent hypoxia. This heterogeneity of OSA is relevant to therapeutic treatment options and we argue the need for better stratification of OSA phenotypes. [ABSTRACT FROM AUTHOR]

Despite profound diaphragm weakness, peak inspiratory pressure‐generating capacity is preserved in young mdx mice revealing adequate compensation by extra‐diaphragmatic muscles of breathing in early dystrophic disease. We hypothesised that loss of compensation gives rise to respiratory system compromise in advanced dystrophic disease. Studies were performed in male wild‐type (n = 196) and dystrophin‐deficient mdx mice (n = 188) at 1, 4, 8, 12 and 16 months of age. In anaesthetised mice, inspiratory pressure and obligatory and accessory respiratory EMG activities were recorded during baseline and sustained tracheal occlusion for up to 30–40 s to evoke peak system activation to task failure. Obligatory inspiratory EMG activities were lower in mdx mice across the ventilatory range to peak activity, emerging in early dystrophic disease. Early compensation protecting peak inspiratory pressure‐generating capacity in mdx mice, which appears to relate to transforming growth factor‐β1‐dependent fibrotic remodelling of the diaphragm and preserved accessory muscle function, was lost at 12 and 16 months of age. Denervation and surgical lesion of muscles of breathing in 4‐month‐old mice revealed a greater dependency on diaphragm for peak inspiratory performance in wild‐type mice, whereas mdx mice were heavily dependent upon accessory muscles (including abdominal muscles) for peak performance. Accessory EMG activities were generally preserved or enhanced in young mdx mice, but peak EMG activities were lower than wild‐type by 12 months of age. In general, ventilation was reasonably well protected in mdx mice until 16 months of age. Despite the early emergence of impairments in the principal obligatory muscles of breathing, peak inspiratory performance is compensated in early dystrophic disease due to diaphragm remodelling and facilitated contribution by accessory muscles of breathing. Loss of compensation afforded by accessory muscles underpins the emergence of respiratory system morbidity in advanced dystrophic disease. Key points: Despite diaphragm weakness, peak inspiratory performance is preserved in young dystrophin‐deficient mdx mice revealing adequate compensation by extra‐diaphragmatic muscles.Peak obligatory muscle (diaphragm, external intercostal, and parasternal intercostal) EMG activities are lower in mdx mice, emerging early in dystrophic disease, before the temporal decline in peak performance. Peak EMG activities of some accessory muscles are lower, whereas others are preserved. There is greater recruitment of the trapezius muscle in mdx mice during peak system activation.In phrenicotomised mice with confirmed diaphragm paralysis, there is a greater contribution made by extra‐diaphragmatic muscles to peak inspiratory pressure in mdx compared with wild‐type mice. Surgical lesion of accessory (including abdominal) muscles adversely affects peak pressure generation in mdx mice.Diaphragm remodelling leading to stiffening provides a mechanical advantage to peak pressure generation via the facilitated action of extra‐diaphragmatic muscles in early dystrophic disease. Peak accessory EMG activities are lower in 12‐month‐old mdx compared to wild‐type mice. Peak inspiratory pressure declines in mdx mice with advanced disease.We conclude that compensation afforded by accessory muscles of breathing declines in advanced dystrophic disease precipitating the emergence of respiratory system dysfunction. [ABSTRACT FROM AUTHOR]

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-CybbTM1Din/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. [ABSTRACT FROM AUTHOR]

The article comments on the study "Champions of the Mountains: Superior Aerobic Performance in Tibetans Is Not Due to Enhanced Cardiopulmonary Traits," by Ben T. Murphy and Ken D. O'Halloran. Topics mentioned include the role of improved diffusion of oxygen to muscle mitochondria, the key determinants of aerobic exercise, and the structural adaptations in the microvasculature of skeletal muscle.

This document is an editorial from the Journal of Physiology discussing the use of chloral hydrate in animal experimentation. The editorial emphasizes the importance of the 3Rs (replacement, reduction, and refinement) principles in laboratory animal research and the need for researchers to adhere to high standards of animal welfare. It highlights that chloral hydrate is considered unacceptable for recovery surgery due to its irritating effects on the gastrointestinal tract and raises concerns about its use for non-recovery experiments and euthanasia. The Journal now calls for the discontinuation of all uses of chloral hydrate, as better alternatives are available. [Extracted from the article]