Hypoxia-induced cardiac injury in dystrophic mice

Zachary Stelter, Jana Strakova, Amritha Yellamilli, Kaleb Fischer, Katharine M Sharpe, DeWayne Townsend

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)H938-H948
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume310
Issue number7
DOIs
StatePublished - Apr 2016

Bibliographical note

Funding Information:
This work was supported by Muscular Dystrophy Association Grant 351960 and National Heart, Lung, and Blood Institute Grants K08-HL102066 and R01-HL114832 to D. Townsend.

Publisher Copyright:
© 2016 the American Physiological Society.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

  • Duchenne muscular dystrophy
  • Dystrophic cardiomyopathy
  • Dystrophin
  • Hypoxia
  • Mitochondria

Fingerprint Dive into the research topics of 'Hypoxia-induced cardiac injury in dystrophic mice'. Together they form a unique fingerprint.

Cite this