Cargando…

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

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 mut...

Descripción completa

Detalles Bibliográficos
Autores principales: Brescia, Marcella, Chao, Ying-Chi, Koschinski, Andreas, Tomek, Jakub, Zaccolo, Manuela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582831/
https://www.ncbi.nlm.nih.gov/pubmed/32992747
http://dx.doi.org/10.3390/ijms21197056
_version_ 1783599281028988928
author Brescia, Marcella
Chao, Ying-Chi
Koschinski, Andreas
Tomek, Jakub
Zaccolo, Manuela
author_facet Brescia, Marcella
Chao, Ying-Chi
Koschinski, Andreas
Tomek, Jakub
Zaccolo, Manuela
author_sort Brescia, Marcella
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7582831
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-75828312020-10-28 Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy Brescia, Marcella Chao, Ying-Chi Koschinski, Andreas Tomek, Jakub Zaccolo, Manuela Int J Mol Sci Article 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. MDPI 2020-09-25 /pmc/articles/PMC7582831/ /pubmed/32992747 http://dx.doi.org/10.3390/ijms21197056 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Brescia, Marcella
Chao, Ying-Chi
Koschinski, Andreas
Tomek, Jakub
Zaccolo, Manuela
Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy
title Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy
title_full Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy
title_fullStr Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy
title_full_unstemmed Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy
title_short Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy
title_sort multi-compartment, early disruption of cgmp and camp signalling in cardiac myocytes from the mdx model of duchenne muscular dystrophy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582831/
https://www.ncbi.nlm.nih.gov/pubmed/32992747
http://dx.doi.org/10.3390/ijms21197056
work_keys_str_mv AT bresciamarcella multicompartmentearlydisruptionofcgmpandcampsignallingincardiacmyocytesfromthemdxmodelofduchennemusculardystrophy
AT chaoyingchi multicompartmentearlydisruptionofcgmpandcampsignallingincardiacmyocytesfromthemdxmodelofduchennemusculardystrophy
AT koschinskiandreas multicompartmentearlydisruptionofcgmpandcampsignallingincardiacmyocytesfromthemdxmodelofduchennemusculardystrophy
AT tomekjakub multicompartmentearlydisruptionofcgmpandcampsignallingincardiacmyocytesfromthemdxmodelofduchennemusculardystrophy
AT zaccolomanuela multicompartmentearlydisruptionofcgmpandcampsignallingincardiacmyocytesfromthemdxmodelofduchennemusculardystrophy