Abstract
Duchenne muscular dystrophy (DMD) is the most frequent and severe form of muscular dystrophy. The disease presents with progressive body-wide muscle deterioration and, with recent advances in respiratory care, cardiac involvement is an important cause of morbidity and mortality. DMD is caused by mutations in the dystrophin gene resulting in the absence of dystrophin and, consequently, disturbance of other proteins that form the dystrophin-associated protein complex (DAPC), including neuronal nitric oxide synthase (nNOS). The molecular mechanisms that link the absence of dystrophin with the alteration of cardiac function remain poorly understood but disruption of NO-cGMP signalling, mishandling of calcium and mitochondrial disturbances have been hypothesized to play a role. cGMP and cAMP are second messengers that are key in the regulation of cardiac myocyte function and disruption of cyclic nucleotide signalling leads to cardiomyopathy. cGMP and cAMP signals are compartmentalised and local regulation relies on the activity of phosphodiesterases (PDEs). Here, using genetically encoded FRET reporters targeted to distinct subcellular compartments of neonatal cardiac myocytes from the DMD mouse model mdx, we investigate whether lack of dystrophin disrupts local cyclic nucleotide signalling, thus potentially providing an early trigger for the development of cardiomyopathy. Our data show a significant alteration of both basal and stimulated cyclic nucleotide levels in all compartments investigated, as well as a complex reorganization of local PDE activities.
Highlights
Duchenne muscular dystrophy (DMD), one of the most common forms of muscular dystrophy, is caused by recessive mutations in the dystrophin gene on the X chromosome and affects 1 in 3500–5000 newborn males worldwide [1]
To avoid confounding effects on cyclic nucleotide signalling that may be secondary to the cardiac remodelling process rather than being a more direct consequence of the lack of dystrophin, we studied ventricular myocytes from neonatal mice (NVM)
To monitor local cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) levels we used already available or newly developed fluorescence resonance energy transfer (FRET)-based reporters that are either distributed in the bulk cytosol or are targeted to the plasmalemma (PM) or to the outer mitochondrial membrane (OMM), three compartments that are thought to be relevant to the pathogenesis of DMD
Summary
Duchenne muscular dystrophy (DMD), one of the most common forms of muscular dystrophy, is caused by recessive mutations in the dystrophin gene on the X chromosome and affects 1 in 3500–5000 newborn males worldwide [1]. In skeletal and cardiac muscle, dystrophin associates with several proteins forming the dystrophin-associated protein complex (DAPC) This complex localizes at the plasmalemma and links the actin cytoskeleton to the extracellular matrix, playing an important structural role. Studies investigating the role of cAMP in skeletal muscle from DMD patients reported a defective response to catecholamines and suggested its involvement in the pathogenesis of the disease [15,16,17] but understanding of how cAMP signalling is affected in dystrophic cardiac myocytes is limited. We investigate the hypothesis that the structural changes that result from the lack of dystrophin may lead to disarray of local cyclic nucleotide signalling in dystrophic cardiac myocytes
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