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Duchenne Muscular Dystrophy: Pathophysiological Implications of Mitochondrial Calcium Signaling and ROS Production

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project title
Duchenne Muscular Dystrophy: Pathophysiological Implications of Mitochondrial Calcium Signaling and ROS Production

abstract
Background: Duchenne muscular dystrophy (DMD) is one of the most common and severe forms of degenerative muscle diseases. It is characterized by progressive muscle weakness and degeneration. Although the primary defect in DMD is the loss of dystrophin, the secondary molecular machinery leading to progressive muscle damage is not understood. Furthermore, it is important that about 10-20% of the patients succumb from the cardiac muscle phenotype of this disease. In both, skeletal and cardiac muscle, force generation is known to be impaired, and there is evidence that Ca signaling is affected by the disease in both tissues. The pathways and structures for Ca signaling are very similar in skeletal and cardiac muscle, from the cellular to the molecular level. Nevertheless, the pathophysiological mechanisms leading to the disease phenotype might be quite diverse in the two tissues. While a substantial body of literature is available on the basic mechanisms and clinical aspects of the skeletal muscle disease, published information about the cardiac myopathy is very scarce.

Working Hypothesis: Based on the available background information and on our own preliminary data, the hypothesis is formulated that in both, the skeletal and cardiac muscle DMD phenotype, an alteration of the Ca signaling system is involved in the pathophysiology and development of the disease. In particular, we hypothesize that in skeletal muscle dystrophy mitochondrial dysfunctions result in a deleterious amplification of stress-induced cytosolic Ca signals and in an amplification of stress-induced ROS production. In cardiac muscle, we will test the hypothesis that reduced expression of calsequestrin and other Ca signaling proteins leads to reduced SR Ca release and lower EC-coupling gain, ultimately impairing cardiac muscle performance.

General Aims: The collaborative study aims at 1) an understanding of the DMD Ca signaling pathophysiology in skeletal muscle on the cellular and molecular level and 2) in an initial characterization of the Ca signaling impairments in cardiomyocytes on the cellular level.

Experimental Design and Methods: With our sophisticated instrumentation and the combination of biophysical techniques and molecular biology methodology, we are in the unique position to carry out experiments that are not possible in most other laboratories. Using a widely employed model animal for this disease, we will carry out biophysical experiments in skeletal and cardiac muscle cells isolated from mdx mice lacking dystrophin. These experiments include spatially resolved assessments and manipulations of cytosolic and mitochondrial Ca signals, quantification of ROS production under various conditions as well as the characterization of cardiac excitation-contraction (EC)-coupling gain in cardiomyocytes isolated from wild-type and mdx mice.

Expected Value of the Proposed Project: Obviously, the results obtained in this study will be pertinent for our understanding of the pathophysiology of DMD, both for the skeletal and cardiac muscle manifestations of the disease. The proposed experiments will provide us with new information and bring us one step closer to the understanding of a whole range of hereditary and acquired muscle disorders associated with metabolic and mitochondrial dysfunctions and cardiac Ca mishandling, including DMD. We hope that this will open new avenues for pharmacological strategies to slow down the progression of these diseases, especially in early stages when muscle degeneration and tissue fibrosis are not yet pronounced. This project is made possible by support from the Swiss Foundation for Research on Muscle Diseases (SSEM).

project team
Prof. Dr. Ernst Niggli (PL), Prof. Dr. Natalia Shirokova (PL), Dr. Mohammed Fanchaouy, Dr. Nina Ullrich, PhD student Carole Jung, Dr. Adriano Martins

partner
Univ. of Medicine and Dentistry, Newark, NJ UNITED STATES

publication
Lindegger & Niggli, J Physiol 2005
Isaeva et al., J Physiol. 2005
Shkryl & Shirokova, J Physiol 2005
Niggli&Shirokova;, Cell Calcium 2007
Jung, Martins, Niggli, Shirokova, Cardiovascular Research, 2008
project duration
01.2006 – 12.2008
state:completed

university unit
Institut für Physiologie

research area
Medicine, Biophysics

index terms
Muscle, dystrophy, cardiac, skeletal, calcium, excitation contraction coupling

last update: 10.02.2009

Projekt-Kontakt
E-Mail

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