Wang, H;
Marrosu, E;
Brayson, D;
Wasala, NB;
Johnson, EK;
Scott, CS;
Yue, Y;
... Montanaro, F; + view all
(2021)
Proteomic analysis identifies key differences in the cardiac interactomes of dystrophin and micro-dystrophin.
Human Molecular Genetics
10.1093/hmg/ddab133.
(In press).
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Abstract
ΔR4-R23/ΔCT micro-dystrophin (μDys) is a miniaturized version of dystrophin currently evaluated in a Duchenne muscular dystrophy (DMD) gene therapy trial to treat skeletal and cardiac muscle disease. In pre-clinical studies, μDys efficiently rescues cardiac histopathology, but only partially normalizes cardiac function. To gain insights into factors that may impact the cardiac therapeutic efficacy of μDys, we compared by mass spectrometry the composition of purified dystrophin and μDys protein complexes in the mouse heart. We report that compared to dystrophin, μDys has altered associations with α1- and β2-syntrophins, as well as cavins, a group of caveolae-associated signaling proteins. In particular, we found that membrane localization of cavins −1 and − 4 in cardiomyocytes requires dystrophin and is profoundly disrupted in the heart of mdx^{5cv} mice,a model of DMD. Following cardiac stress/damage, membrane-associated cavin-4 recruits the signaling molecule ERK to caveolae, which activates key cardio-protective responses. Evaluation of ERK signaling revealed a profound inhibition, below physiological baseline, in the mdx^{5cv} mouse heart. Expression of μDys in mdx^{5cv} mice prevented the development of cardiac histopathology but did not rescue membrane localization of cavins nor did it normalize ERK signaling. Our study provides the first comparative analysis of purified protein complexes assembled in vivo by full-length dystrophin and a therapeutic micro-dystrophin construct. This has revealed disruptions in cavins and ERK signaling that may contribute to DMD cardiomyopathy. This new knowledge is important for ongoing efforts to prevent and treat heart disease in DMD patients.
| Type: | Article |
|---|---|
| Title: | Proteomic analysis identifies key differences in the cardiac interactomes of dystrophin and micro-dystrophin |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/hmg/ddab133 |
| Publisher version: | https://doi.org/10.1093/hmg/ddab133 |
| Language: | English |
| Additional information: | © The Author(s) 2021. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | cardiac myocytes, myocardium, cardiomyopathy, signal transduction, gene therapy, heart diseases, duchenne's muscular dystrophy, caveolae, dystrophin, tissue membrane, mass spectrometry, heart, mice, microbiology procedures stress, cardiac function, signaling protein, histopathology tests, molecule, complex |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10127458 |
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