Mechanical and non-mechanical functions of Dystrophin can prevent cardiac abnormalities in Drosophila

Abstract

Dystrophin-deficiency causes cardiomyopathies and shortens the life expectancy of Duchenne and Becker muscular dystrophy patients. Restoring Dystrophin expression in the heart by gene transfer is a promising avenue to explore as a therapy. Truncated Dystrophin gene constructs have been engineered and shown to alleviate dystrophic skeletal muscle disease, but their potential in preventing the development of cardiomyopathy is not fully understood. In the present study, we found that either the mechanical or the signaling functions of Dystrophin were able to reduce the dilated heart phenotype of Dystrophin mutants in a Drosophila model. Our data suggest that Dystrophin retains some function in fly cardiomyocytes in the absence of a predicted mechanical link to the cytoskeleton. Interestingly, cardiac-specific manipulation of nitric oxide synthase expression also modulates cardiac function, which can in part be reversed by loss of Dystrophin function, further implying a signaling role of Dystrophin in the heart. These findings suggest that the signaling functions of Dystrophin protein are able to ameliorate the dilated cardiomyopathy, and thus might help to improve heart muscle function in micro-Dystrophin-based gene therapy approaches.

X-Linked Dilated Cardiomyopathy: A Cardiospecific Phenotype of Dystrophinopathy

“…Taghli-Lamallem, et al reported that either the mechanical or the signaling functions of dystrophin reduced the dilated heart phenotype of dystrophin mutants in a drosophila model, and dystrophin retained some function in the absence of a predicted mechanical link to the cytoskeleton [ 79 ]. Cardiospecific manipulation of NOS expression modulates cardiac function, which can be reversed in part by the loss of the dystrophin function, further supporting the potential signaling role of dystrophin in the heart [ 80 ].…”

Inter-Species Rescue of Mutant Phenotype—The Standard for Genetic Analysis of Human Genetic Disorders in Drosophila melanogaster Model

“…Other cardiac disorders have been modelled in D. melanogaster , such as channelopathies [ 163 , 164 , 165 , 166 , 167 ] and different syndromic [ 168 , 169 , 170 ] or nonsyndromic cardiomyopathies [ 171 , 172 , 173 , 174 , 175 , 176 , 177 ]. To our knowledge, currently, none of these diseases benefit from effective human allele-based functional complementation studies, although some groups successfully tackled the heterologous rescuing of fly cardiac phenotype, the alleles of choice being of animal origin, mainly from mice [ 173 , 178 , 179 ]. For example, Gao’s group reversed the effect of loss of fly γ-sarcoglycan ( Scgδ ) by using a murine counterpart gamma-sarcoglycan ( Sgcg ) [ 179 ].…”

“…The previously presented data, as well as data from Table 2, demonstrate the structural and functional homologies between fruit fly and human cardiac genes and advocate the use of D. melanogaster system as a prime candidate to study and validate genetic variants associated with cardiac disorders. [173,178] Noonan syndrome (h)PTPN11 (SHP-2) csw csw mutations determine zygotic lethality expression of (h)SHP-2 rescues the zygotic lethality [190] muscle and aortic defects, ARIH1-related (h)ARIH1 ari-1 ari-1-null allele is associated with affected larval muscle, lethality or reduced lifespan in adults (h)ARIH1 rescues ari-1-related lethality.…”

Quel avenir pour la dystrophine ?

“…Ces protéines en interaction avec la dystrophine sont alors classées comme des glycoprotéines et/ou simplement des protéines associées. Un récent bilan actualisé pour mieux saisir la complexité de l'arrangement architectural autour de la membrane et du complexe entre dystrophine et ses multiples partenaires figure dans la récente étude citée en référence avec les principales voies de signalisation impliquées au sein du muscle cardiaque [22]. C'est cependant dans le muscle squelettique plus particulièrement au niveau des costamères Cependant, les connaissances acquises ne vont pas se limiter à la découverte de nouveaux partenaires mais aussi à la dystrophine elle-même.…”