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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\u2013axial tubule system (TATS) structure and on Ca2+ homeostasis in the heart.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>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 \u03b2-adrenergic receptor stimulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/europace\/euaa093","type":"journal-article","created":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T07:09:28Z","timestamp":1585897768000},"page":"1119-1131","source":"Crossref","is-referenced-by-count":26,"title":["Dysferlin links excitation\u2013contraction coupling to structure and maintenance of the cardiac transverse\u2013axial tubule system"],"prefix":"10.1093","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2774-1661","authenticated-orcid":false,"given":"Julia","family":"Hofhuis","sequence":"first","affiliation":[{"name":"Department of Child and Adolescent Health, University Medical Center G\u00f6ttingen, Robert-Koch-Stra\u00dfe 40, 37075 G\u00f6ttingen, Germany"},{"name":"DZHK (German Center for Cardiovascular Research), Partner Sites G\u00f6ttingen and Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Bersch","sequence":"first","affiliation":[{"name":"Department of Child and Adolescent Health, University Medical Center G\u00f6ttingen, Robert-Koch-Stra\u00dfe 40, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Wagner","sequence":"first","affiliation":[{"name":"Department of Cardiology, University Hospital Regensburg, Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Molina","sequence":"first","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), Partner Sites G\u00f6ttingen and Hamburg, Germany"},{"name":"Institute of Pharmacology and Toxicology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"},{"name":"Institute for Experimental Cardiology, University Medical Center Hamburg, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Funsho E","family":"Fakuade","sequence":"first","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavanya M","family":"Iyer","sequence":"first","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), Partner Sites G\u00f6ttingen and Hamburg, Germany"},{"name":"Institute of Pharmacology and Toxicology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"},{"name":"Computational and Systems Biology, Genome Institute of Singapore, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Streckfuss-B\u00f6meke","sequence":"first","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), Partner Sites G\u00f6ttingen and Hamburg, Germany"},{"name":"Department of Cardiology and Pneumonology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Toischer","sequence":"first","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), Partner Sites G\u00f6ttingen and Hamburg, Germany"},{"name":"Department of Cardiology and Pneumonology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura C","family":"Zelaray\u00e1n","sequence":"first","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), Partner Sites G\u00f6ttingen and Hamburg, Germany"},{"name":"Institute of Pharmacology and Toxicology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels","family":"Voigt","sequence":"first","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), Partner Sites G\u00f6ttingen and Hamburg, Germany"},{"name":"Institute of Pharmacology and Toxicology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viacheslav O","family":"Nikolaev","sequence":"first","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), Partner Sites G\u00f6ttingen and Hamburg, Germany"},{"name":"Institute of Pharmacology and Toxicology, University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany"},{"name":"Institute for Experimental Cardiology, University Medical Center Hamburg, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars S","family":"Maier","sequence":"first","affiliation":[{"name":"Department of Cardiology, University Hospital Regensburg, Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Klinge","sequence":"first","affiliation":[{"name":"Department of Child and Adolescent 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