title: Cardiac and respiratory dysfunction in Duchenne muscular dystrophy and the role of second messengers.
abstract: Duchenne muscular dystrophy (DMD) affects young boys and is characterized by the absence of dystrophin, a large cytoskeletal protein present in skeletal and cardiac muscle cells and neurons. The heart and diaphragm become necrotic in DMD patients and animal models of DMD, resulting in cardiorespiratory failure as the leading cause of death. The major consequences of the absence of dystrophin are high levels of intracellular Ca(2+) and the unbalanced production of NO that can finally trigger protein degradation and cell death. Cytoplasmic increase in Ca(2+) concentration directly and indirectly triggers different processes such as necrosis, fibrosis, and activation of macrophages. The absence of the neuronal isoform of nitric oxide synthase (nNOS) and the overproduction of NO by the inducible isoform (iNOS) further increase the intracellular Ca(2+) via a hypernitrosylation of the ryanodine receptor. NO overproduction, which further induces the expression of iNOS but decreases the expression of the endothelial isoform (eNOS), deregulates the muscle tissue blood flow creating an ischemic situation. The high levels of Ca(2+) in dystrophic muscles and the ischemic state of the muscle tissue would culminate in a positive feedback loop. While efforts continue toward optimizing cardiac and respiratory care of DMD patients, both Ca(2+) and NO in cardiac and respiratory muscle pathways have been shown to be important to the etiology of the disease. Understanding the mechanisms behind the fine regulation of Ca(2+) -NO may be important for a noninterventional and noninvasive supportive approach to treat DMD patients, improving the quality of life and natural history of DMD patients.
authors: Medical Biophysics Unit, Institute of Physiology and Pathophysiology, INF326, Heidelberg University, 69120 Heidelberg, Germany. matias@physiologie.uni-heidelberg.de
authors: Matias
authors: M
authors: Mosqueira
authors: Ulrike
authors: U
authors: Zeiger
authors: Moritz
authors: M
authors: Förderer
authors: Heinrich
authors: H
authors: Brinkmeier
authors: Rainer H A
authors: RH
authors: Fink
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000378:metabolism; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000503:physiopathology*; D015290:Second Messenger Systems
chemical_list: D006023:Glycoproteins
keywords: Ca2+-NO signaling; cardiomyopathy; dystrophin; skeletal muscle; ventilation