Duchenne muscular dystrophy (DMD), a fatal and crippling disease, results from a mutation of the membrane stabilizing protein dystrophin. Dystrophin-deficient muscles are more susceptible than normal to a variety of stresses. The respiratory muscles are critical for survival and their failure is a leading cause of death in DMD. Sleep disturbed breathing (SDB) is common and nocturnal gas exchange abnormalities and disrupted sleep architecture, hallmarks of SDB, have been reported in >80% of DMD patients. Reduced ventilation during sleep results in cyclic decreases in arterial oxygen tensions (hypoxia), in elevations of several inflammatory cytokines including TNF-1, and in the production of reactive oxygen species (ROS), all of which can putatively impact muscle cell function. In addition, physiologic responses to cyclic alterations in oxygen levels that accompany SDB include increased sympathetic discharge and enhanced activation of the respiratory muscles (upper airway and ventilatory), factors which can also impact muscle function. Despite the pervasiveness of SDB in DMD patients, the effects of SDB on respiratory muscle function in DMD remain unknown. We hypothesize that SDB exacerbates dysfunction of the respiratory muscle in DMD. Preliminary data in dystrophic mice (Dmdmdx) reveal that experimental sleep apnea intensifies functional declines in diaphragm contractility. Proposed studies will delineate mechanical and biochemical mechanisms responsible for SDB induced respiratory muscle dysfunction in an animal model of DMD. More specifically, the proposed studies will assess 1) the putative impact of enhanced muscle recruitment (mechanical stress) in response to episodic hypoxia on respiratory muscle function;2) to assess the putative role mediated by TNF-1 mechanisms;and 3) to assess the role attributed to oxidative stress in mediating SDB dysfunction of dystrophin-deficient respiratory muscles. To this end, SDB will be simulated in Dmdmdx- mice with long term (up to 12 weeks) diurnal (8 hrs per day, 5 days a week) exposure to experimental sleep apnea (episodic hypoxia). The dysfunction of the respiratory muscles will be assessed by measuring functional parameters (breathing strategies, force output and fatigability of isolated muscle bundles), biochemical markers (collagen content, lipid peroxidation, and inflammatory cytokines), and histological/ morphometric markers (central nucleation, fiber size, and extent of fiber loss and fibrosis).
. Sleep disordered breathing (SDB) is prevalent in Duchenne Muscular Dystrophy (DMD) and may exacerbate dysfunction of the respiratory muscles. Studies will investigate several putative mechanisms (mechanical and biochemical stressors) that contribute to respiratory muscle dysfunction using Dmdmdx-mice. Since respiratory muscle failure is a leading cause of death in DMD, these studies will reveal new therapeutic modalities aimed at preventing respiratory muscle failure in DMD.
| Chaudhari, Milind R; Fallavollita, James A; Farkas, Gaspar A (2016) The Effects of Experimental Sleep Apnea on Cardiac and Respiratory Functions in 6 and 18 Month Old Dystrophic (mdx) Mice. PLoS One 11:e0147640 |
