title: Hypoxia-induced cardiac injury in dystrophic mice.
abstract: Duchenne muscular dystrophy (DMD) is a disease of progressive destruction of striated muscle, resulting in muscle weakness with progressive respiratory and cardiac failure. Respiratory and cardiac disease are the leading causes of death in DMD patients. Previous studies have suggested an important link between cardiac dysfunction and hypoxia in the dystrophic heart; these studies aim to understand the mechanism underlying this connection. Here we demonstrate that anesthetized dystrophic mice display significant mortality following acute exposure to hypoxia. This increased mortality is associated with a significant metabolic acidosis, despite having significantly higher levels of arterial Po2 Chronic hypoxia does not result in mortality, but rather is characterized by marked cardiac fibrosis. Studies in isolated hearts reveal that the contractile function of dystrophic hearts is highly susceptible to short bouts of ischemia, but these hearts tolerate prolonged acidosis better than wild-type hearts, indicating an increased sensitivity of the dystrophic heart to hypoxia. Dystrophic hearts display decreased cardiac efficiency and oxygen extraction. Isolated dystrophic cardiomyocytes and hearts have normal levels of FCCP-induced oxygen consumption, and mitochondrial morphology and content are normal in the dystrophic heart. These studies demonstrate reductions in cardiac efficiency and oxygen extraction of the dystrophic heart. The underlying cause of this reduced oxygen extraction is not clear; however, the current studies suggest that large disruptions of mitochondrial respiratory function or coronary flow regulation are not responsible. This finding is significant, as hypoxia is a common and largely preventable component of DMD that may contribute to the progression of the cardiac disease in DMD patients.
authors: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota.
authors: Zachary
authors: Z
authors: Stelter
authors: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota.
authors: Jana
authors: J
authors: Strakova
authors: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota.
authors: Amritha
authors: A
authors: Yellamilli
authors: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota.
authors: Kaleb
authors: K
authors: Fischer
authors: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota.
authors: Katharine
authors: K
authors: Sharpe
authors: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota town0045@umn.edu.
authors: DeWayne
authors: D
authors: Townsend
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005355:Fibrosis; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology*; D051379:Mice; D018101:Mice, Inbred mdx; D008929:Mitochondria, Heart / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000503:physiopathology*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism
chemical_list: D010100:Oxygen
keywords: Duchenne muscular dystrophy; dystrophic cardiomyopathy; dystrophin; hypoxia; mitochondria