Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are widespread and severe forms of striated muscle diseases caused by dystrophin gene mutations. They are characterized by progressive degeneration of muscle function. Cardiac abnormality is present in the majority of boys with DMD and BMD by age 20. Heart failure is the second leading cause of fatalities. With improving therapeutic options for the skeletal muscle weakness, cardiac disease becomes increasingly limiting for the survival of the young patients. Further prolongation of their life depends on a mechanistic understanding of the cardiac defects. In dystrophic heart, force generation is known to be impaired. The pathoanatomic basis for the loss of function is mainly the replacement of myocardium by connective tissue and fat (fibrosis). Our preliminary findings indicate that augmented Ca2+ signaling, Na+ overload and oxidative/nitrosative stress play an important role in the development of contractile dysfunction and progressive damage of dystrophic cardiac tissue. Our observations led us to three hypotheses that will be tested in this project: 1). Excessive Ca2+ signals arise from an elevated RyR sensitivity to Ca2+. 2). Elevated RyR Ca2+ sensitivity is compatible with or even ensures reliability of EC-coupling at the onset of the disease. During the progression of the disease however, this initially beneficial change becomes maladaptive and contributes to the deterioration of cardiac muscle function. 3a). An elevated [Na+]i limits the ability of the sarcolemmal Na+-Ca2+ exchanger to extrude Ca2+ from dystrophic cardiac myocytes, thus promoting Ca2+ accumulation in the cytosol and consequently cellular damage. 2b). An increase in [Na+]i enhances Ca2+ removal from the mitochondria, decreases mitochondrial Ca2+ accumulation and changes mitochondrial metabolic state. In three intimately connected Specific Aims we will 1) determine the mechanisms underlying changes in the sensitivity of RyR, 2) examine alterations of EC-coupling during development of cardiac dystrophy and 3) evaluate changes in intracellular Na+ handling and establish how they affect cytosolic and mitochondrial Ca2+ signaling and mitochondrial metabolic state. To achieve these goals a multitude of imaging, electrophysiological, and biochemical techniques will be used. The experiments will be carried out on cardiomyocytes isolated from the animals of different age groups in order to establish a correlation and possibly causal relationship between cellular abnormalities and the development of cardiac myopathy. Two animal models of dystrophy will be employed: mdx mice, lacking dystrophin, and mdx/utrophin-/- mice, in which utrophin has also been knocked out. Our overall hypothesis is that cardiac myopathy in muscular dystrophy is a slowly developing pathology due to the cumulative effects of multiple defects in Ca2+ signaling and Na+ handling. This proposal will identify the key cellular processes contributing to the defects and provide a solid basis for developing therapeutic intervention.

Public Health Relevance

Cardiac abnormalities are the second leading cause of death of the patients with Duchenne and Becker muscular dystrophy, the two most widespread and severe forms of degenerative muscle diseases. Unfortunately, very little is presently known about the mechanisms causing the heart failure in these patients. With this basic science project we hope to contribute significantly to translational research in the field of cardiac myopathies and to help to bridge the gap from the molecular defect underlying muscular dystrophy to the bedside.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093342-02
Application #
8246991
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Kaltman, Jonathan R
Project Start
2011-04-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$390,000
Indirect Cost
$140,000
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Kyrychenko, Sergii; Polakova, Eva; Kang, Chifei et al. (2013) Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy. Cardiovasc Res 97:666-75
Shirokova, Natalia; Niggli, Ernst (2013) Cardiac phenotype of Duchenne Muscular Dystrophy: insights from cellular studies. J Mol Cell Cardiol 58:217-24
Tjondrokoesoemo, Andoria; Li, Na; Lin, Pei-Hui et al. (2013) Type 1 inositol (1,4,5)-trisphosphate receptor activates ryanodine receptor 1 to mediate calcium spark signaling in adult mammalian skeletal muscle. J Biol Chem 288:2103-9
Niggli, Ernst; Ullrich, Nina D; Gutierrez, Daniel et al. (2013) Posttranslational modifications of cardiac ryanodine receptors: Ca(2+) signaling and EC-coupling. Biochim Biophys Acta 1833:866-75