Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy

被引:12
作者
Brescia, Marcella [1 ]
Chao, Ying-Chi [1 ]
Koschinski, Andreas [1 ]
Tomek, Jakub [1 ]
Zaccolo, Manuela [1 ]
机构
[1] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3PT, England
关键词
Duchenne muscular dystrophy; cAMP; cGMP; NO; phosphodiesterases; cardiomyopathy; fluorescence resonance energy transfer; signalling compartmentalisation; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; NITRIC-OXIDE SYNTHASE; MOUSE MODEL; SKELETAL; SILDENAFIL; CYCLASE; NETWORK; HEART; CARDIOMYOPATHY; STIMULATION;
D O I
10.3390/ijms21197056
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:1 / 19
页数:19
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