Journal Article

FZJ-2019-01683

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Desmoglein 2 mutation provokes skeletal muscle actin expression and accumulation at intercalated discs in murine hearts

Kant, S. (Corresponding author) ; Freytag, B. ; Herzog, A. ; Reich, A. ; Merkel, R.FZJ* ; Hoffmann, B.FZJ* ; Krusche, C. A. ; Leube, R. E.

2019
Company of Biologists Limited Cambridge

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Please use a persistent id in citations: http://hdl.handle.net/2128/22881  doi:10.1242/jcs.199612

Abstract: Arrhythmogenic cardiomyopathy (AC) is an incurable progressive disease that is linked to mutations in genes coding for components of desmosomal adhesions that are localized to the intercalated disc region, which electromechanically couples adjacent cardiomyocytes. To date, the underlying molecular dysfunctions are not well characterized. In two murine AC models, we find an upregulation of the skeletal muscle actin gene (Acta1), which is known to be a compensatory reaction to compromised heart function. Expression of this gene is elevated prior to visible morphological alterations and clinical symptoms, and persists throughout pathogenesis with an additional major rise during the chronic disease stage. We provide evidence that the increased Acta1 transcription is initiated through nuclear activation of the serum response transcription factor (SRF) by its transcriptional co-activator megakaryoblastic leukemia 1 protein (MKL1, also known as MRTFA). Our data further suggest that perturbed desmosomal adhesion causes Acta1 overexpression during the early stages of the disease, which is amplified by transforming growth factor β (TGFβ) release from fibrotic lesions and surrounding cardiomyocytes during later disease stages. These observations highlight a hitherto unknown molecular AC pathomechanism.

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Contributing Institute(s):

1. Biomechanik (ICS-7)

Research Program(s):

1. 552 - Engineering Cell Function (POF3-552) (POF3-552)

Appears in the scientific report 2019

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Database coverage:
; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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