Dysferlin links excitation–contraction coupling to structure and maintenance of the cardiac transverse–axial tubule system

• DOI: 10.1093/europace/euaa093
• Publication Date: 2020-04-03T11:09:28Z
• Authors: Julia Hofhuis; Kristina Bersch; Stefan Wagner; Cristina Molina; Funsho E Fakuade; Lavanya M Iyer; Katrin Streckfuss...; Karl Toischer; Laura C Zelarayán; Niels Voigt; Viacheslav O Niko...; Lars S Maier; Lars Klinge; Sven Thoms
• Keywords: Dysferlin; Caveolin 3; Sarcolemma

Abstract Aims The multi-C2 domain protein dysferlin localizes to the T-Tubule system of skeletal and heart muscles. In muscle, is known play a role in membrane repair T-tubule biogenesis maintenance. Dysferlin deficiency manifests as muscular dystrophy proximal distal Cardiomyopathies have been also reported, some dysferlinopathy mouse models develop cardiac dysfunction under stress. Generally, functional relevance not clear. aim this study was analyse effect on transverse–axial tubule (TATS) structure Ca2+ homeostasis heart. Methods results We studied localization rat cardiomyocytes by immunofluorescence microscopy. dysferlin-deficient ventricular cardiomyocytes, we analysed TATS live staining assessed handling patch-clamp experiments measurement transients sparks. found increasing co-localization with L-type Ca2+-channel during development show that leads pathological loss transversal increase longitudinal elements (axialization). detected reduced Ca2+-current (ICa,L) from mice increased frequency spontaneous sarcoplasmic reticulum release events resulting pro-arrhythmic contractions. Moreover, showed an impaired response β-adrenergic receptor stimulation. Conclusions required for maintenance controlling ratio axial elements. Absence defects which may contribute contractile patients.