Effect of episodic hypoxia on cardio-respiratory dysfunction in Duchenne muscular dystrophy
Chaudhari, Milind Ramchandra
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Duchenne muscular dystrophy (DMD) is the most prevalent and the most severe form of muscular dystrophy, affecting approximately 1 out of 3500 males. Along with skeletal muscle damage and weakness, these patients also have cardiac and respiratory dysfunction. The average life expectancy for these patients ranges from the early teens to the mid-30s, and respiratory failure and cardiac failure are most common causes of death. DMD is 100% fatal as there is no known cure for this disease. Sleep is vulnerable period in muscular dystrophy patients and sleep disordered breathing (SDB) is very common (>80%) in DMD patients. Intermittent hypoxia caused by hypoventilation or apneas during sleep lead to cyclic alterations in oxygen tensions and the production of reactive oxygen species (ROS). Responses to the cyclic alterations in oxygen levels include elevations in blood pressure, increased sympathetic discharge, and enhanced recruitment of respiratory muscles and heart. SDB in non-DMD subjects is associated with neurocognitive defects, cardiovascular complications, and respiratory muscle deficits. Therefore, SDB along with sleep apnea cannot be ruled out as a potential cause of cardio-respiratory dysfunction in DMD patients. The mdx mouse, a murine model of DMD presenting with a deficiency of dystrophin, also reveals a progressive myopathy of the diaphragm with compromised ventilatory function. Cardiomyopathy is also observed in mdx mice, but at a later age. The earliest signs of cardiomyopathy are detected in mdx mice at 9-10 months of age and become more prominent with age. Although cardiac and respiratory dysfunctions consistent with DMD are indeed detected in mdx mice, mdx mice do not have spontaneous sleep apnea. Thus, in order to better define the possible consequences of SDB that is so prevalent in DMD, the purpose of the present study was to investigate the impact of episodic hypoxia on respiratory and heart muscle dysfunction in mdx mice and to explore potential mechanical or biochemical stressors (oxidative stress, inflammation) that may be responsible for mediating the change in function. Our results show that episodic hypoxia leads to cardiac and respiratory dysfunction in mdx mice. In addition, the observed dysfunctions were more severe in older mdx mice. Our findings also highlight that episodic hypoxia can have divergent effect on the cardiac and respiratory systems. Indeed, in younger animals, episodic hypoxia produced improvement in diaphragmatic function while producing mild cardiac dysfunction. In older animals, episodic hypoxia proved to be detrimental to both the cardiac and respiratory systems. We found no significant ventilatory dysfunction in 6 month old mdx mice after 12 weeks of EH exposure with nadir FiO 2 6%. However, prednisone treatment exhibited increase in ventilation as compared to control mdx mice. In prednisone treated group, higher ventilation was maintained even after EH exposure. We report that treatment with prednisone tend to show decrease in cardiac function as compared to control mdx mice. However, with exposure to EH, prednisone treated mice showed less severe cardiac dysfunction as compared to untreated mdx mice. Therefore, even though prednisone treatment impairs cardiac function, it can help attenuate the progression of cardiac dysfunction caused by episodic hypoxia. Even though, EH exposure with nadir FiO 2 of 6% did not show diaphragm dysfunction in 6-mth old mdx mice, when exposed to more severe EH (nadir FiO 2 5%), diaphragm dysfunction was detected. Evaluation of possible mechanisms for this dysfunction show that even though oxidative stress is marginally elevated in diaphragms of EH exposed mdx mice, inflammation seems to play a major role in diaphragm dysfunction. Thus, our results show that episodic hypoxia can exacerbate cardiac and respiratory dysfunction in muscular dystrophy. The amount of this dysfunction depends upon the severity of oxygen desaturation during episodic hypoxia and the age of the animal. Inflammation, and to some extent oxidative stress, appears to exert a major role in episodic hypoxia induced cardiac and respiratory dysfunction in mdx mice. However, further studies are needed to investigate the inflammatory markers, or targets for potential therapeutic interventions to decrease morbidity and mortality in DMD.