Dysferlin links excitation-contraction coupling to structure and maintenance of the cardiac transverse-axial tubule system
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Dysferlin links excitation-contraction coupling to structure and maintenance of the cardiac transverse-axial tubule system. / Hofhuis, Julia; Bersch, Kristina; Wagner, Stefan; Molina, Cristina; Fakuade, Funsho E; Iyer, Lavanya M; Streckfuss-Bömeke, Katrin; Toischer, Karl; Zelarayán, Laura C; Voigt, Niels; Nikolaev, Viacheslav O; Maier, Lars S; Klinge, Lars; Thoms, Sven.
In: EUROPACE, Vol. 22, No. 7, 01.07.2020, p. 1119-1131.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Dysferlin links excitation-contraction coupling to structure and maintenance of the cardiac transverse-axial tubule system
AU - Hofhuis, Julia
AU - Bersch, Kristina
AU - Wagner, Stefan
AU - Molina, Cristina
AU - Fakuade, Funsho E
AU - Iyer, Lavanya M
AU - Streckfuss-Bömeke, Katrin
AU - Toischer, Karl
AU - Zelarayán, Laura C
AU - Voigt, Niels
AU - Nikolaev, Viacheslav O
AU - Maier, Lars S
AU - Klinge, Lars
AU - Thoms, Sven
N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - AIMS: The multi-C2 domain protein dysferlin localizes to the T-Tubule system of skeletal and heart muscles. In skeletal muscle, dysferlin is known to play a role in membrane repair and in T-tubule biogenesis and maintenance. Dysferlin deficiency manifests as muscular dystrophy of proximal and distal muscles. Cardiomyopathies have been also reported, and some dysferlinopathy mouse models develop cardiac dysfunction under stress. Generally, the role and functional relevance of dysferlin in the heart is not clear. The aim of this study was to analyse the effect of dysferlin deficiency on the transverse-axial tubule system (TATS) structure and on Ca2+ homeostasis in the heart.METHODS AND RESULTS: We studied dysferlin localization in rat and mouse cardiomyocytes by immunofluorescence microscopy. In dysferlin-deficient ventricular mouse cardiomyocytes, we analysed the TATS by live staining and assessed Ca2+ handling by patch-clamp experiments and measurement of Ca2+ transients and Ca2+ sparks. We found increasing co-localization of dysferlin with the L-type Ca2+-channel during TATS development and show that dysferlin deficiency leads to pathological loss of transversal and increase in longitudinal elements (axialization). We detected reduced L-type Ca2+-current (ICa,L) in cardiomyocytes from dysferlin-deficient mice and increased frequency of spontaneous sarcoplasmic reticulum Ca2+ release events resulting in pro-arrhythmic contractions. Moreover, cardiomyocytes from dysferlin-deficient mice showed an impaired response to β-adrenergic receptor stimulation.CONCLUSIONS: Dysferlin is required for TATS biogenesis and maintenance in the heart by controlling the ratio of transversal and axial membrane elements. Absence of dysferlin leads to defects in Ca2+ homeostasis which may contribute to contractile heart dysfunction in dysferlinopathy patients.
AB - AIMS: The multi-C2 domain protein dysferlin localizes to the T-Tubule system of skeletal and heart muscles. In skeletal muscle, dysferlin is known to play a role in membrane repair and in T-tubule biogenesis and maintenance. Dysferlin deficiency manifests as muscular dystrophy of proximal and distal muscles. Cardiomyopathies have been also reported, and some dysferlinopathy mouse models develop cardiac dysfunction under stress. Generally, the role and functional relevance of dysferlin in the heart is not clear. The aim of this study was to analyse the effect of dysferlin deficiency on the transverse-axial tubule system (TATS) structure and on Ca2+ homeostasis in the heart.METHODS AND RESULTS: We studied dysferlin localization in rat and mouse cardiomyocytes by immunofluorescence microscopy. In dysferlin-deficient ventricular mouse cardiomyocytes, we analysed the TATS by live staining and assessed Ca2+ handling by patch-clamp experiments and measurement of Ca2+ transients and Ca2+ sparks. We found increasing co-localization of dysferlin with the L-type Ca2+-channel during TATS development and show that dysferlin deficiency leads to pathological loss of transversal and increase in longitudinal elements (axialization). We detected reduced L-type Ca2+-current (ICa,L) in cardiomyocytes from dysferlin-deficient mice and increased frequency of spontaneous sarcoplasmic reticulum Ca2+ release events resulting in pro-arrhythmic contractions. Moreover, cardiomyocytes from dysferlin-deficient mice showed an impaired response to β-adrenergic receptor stimulation.CONCLUSIONS: Dysferlin is required for TATS biogenesis and maintenance in the heart by controlling the ratio of transversal and axial membrane elements. Absence of dysferlin leads to defects in Ca2+ homeostasis which may contribute to contractile heart dysfunction in dysferlinopathy patients.
U2 - 10.1093/europace/euaa093
DO - 10.1093/europace/euaa093
M3 - SCORING: Journal article
C2 - 32572487
VL - 22
SP - 1119
EP - 1131
JO - EUROPACE
JF - EUROPACE
SN - 1099-5129
IS - 7
ER -