Abstract
Duchenne muscular dystrophy (DMD) is a fatal disease where over 90% of patients succumb to respiratory or cardiac failure. Sleep apnea and sleep disordered breathing (SDB) are noted in a plurality of DMD patients, and the resulting nocturnal episodic hypoxia (EH) cannot be ruled out as a contributing factor to cardiac and respiratory dysfunction. In this study, we investigated the impact of long-term episodic hypoxia, which mimics the cyclic hypoxia seen in sleep apnea, on cardiac and respiratory function in a murine model of DMD (mdx mice). Since the severity and prevalence of sleep apnea in DMD increases with age, we studied the impact of EH on young (6-month) and on older (18-month) mdx mice. Mice were either exposed for 12 weeks to EH (8 hours/day, 5 days/week) or to room air. We noted a significant increase in left ventricular (LV) dilatation (transthoracic echocardiography) on EH exposure in both age groups, but reduced LV contractility was seen only in 6-month old mice. With EH exposure, an increased fibrosis (hydroxyproline) was noted in both cardiac and diaphragm muscle in 18-month but not 6-month old mice. No significant change in relative diaphragm strength (in-vitro) was noted on EH exposure in 18-month old mice. In contrast, EH exposed 6-month old mice showed a significant increase in relative diaphragm strength. EH exposure did not result in any significant change in ventilatory parameters (barometric plethysmography) in awake 6-month old mdx mice. In contrast, 18-month old mdx mice showed considerable ventilatory dysfunction, consistent with reduced ventilatory reserve. Our findings highlight that sleep apnea impacts respiratory and cardiac function in muscular dystrophy, and that EH can have divergent effects on both systems. To our knowledge, this is the first comprehensive study to investigate the impact of EH on cardiac and respiratory function in mdx mice.
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder that affects approximately 1 out of 3500 male births [1]
Smith et al [7] reported that patients with DMD endure bouts of episodic hypoxia (EH) during sleep, during which SaO2 levels fall from baseline values of 95.4 ± 0.6% to a mean nadir of 74.2 ± 3.9%
In order to better define the possible consequences of sleep disordered breathing (SDB) that is so prevalent in DMD, the current study assessed the putative impact of EH on cardiac and respiratory function in mdx mice
Summary
Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder that affects approximately 1 out of 3500 male births [1]. Smith et al [7] reported that patients with DMD endure bouts of episodic hypoxia (EH) during sleep, during which SaO2 levels fall from baseline values of 95.4 ± 0.6% to a mean nadir of 74.2 ± 3.9%. Cardiac and respiratory dysfunctions consistent with DMD are detected in mdx mice, they do not have spontaneous SDB. In order to better define the possible consequences of SDB that is so prevalent in DMD, the current study assessed the putative impact of EH on cardiac and respiratory function in mdx mice. Since SDB is more severe and prevalent in older DMD patients, we investigated whether the effects of EH in mdx mice are compounded by age. The purpose of this study, was to assess the impact of EH on cardiac and respiratory function in 6 and 18-month old mdx mice. This is the first comprehensive study to investigate the consequences of EH simultaneously on cardiac and respiratory function in young and older mdx mice
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