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dc.contributor.authorLukyanenko, V.
dc.contributor.authorMuriel, J.M.
dc.contributor.authorBloch, R.J.
dc.date.accessioned2019-10-08T19:43:49Z
dc.date.available2019-10-08T19:43:49Z
dc.date.issued2017
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85021335819&doi=10.1113%2fJP274515&partnerID=40&md5=8cf1b0b36031ecfbd2e2e7132555cde3
dc.identifier.urihttp://hdl.handle.net/10713/11077
dc.description.abstractKey points: Dysferlin, the protein missing in limb girdle muscular dystrophy 2B and Miyoshi myopathy, concentrates in transverse tubules of skeletal muscle, where it stabilizes voltage-induced Ca2+ transients against loss after osmotic shock injury (OSI). Local expression of dysferlin in dysferlin-null myofibres increases transient amplitude to control levels and protects them from loss after OSI. Inhibitors of ryanodine receptors (RyR1) and L-type Ca2+ channels protect voltage-induced Ca2+ transients from loss; thus both proteins play a role in injury in dysferlin's absence. Effects of Ca2+-free medium and S107, which inhibits SR Ca2+ leak, suggest the SR as the primary source of Ca2+ responsible for the loss of the Ca2+ transient upon injury. Ca2+ waves were induced by OSI and suppressed by exogenous dysferlin. We conclude that dysferlin prevents injury-induced SR Ca2+ leak. Abstract: Dysferlin concentrates in the transverse tubules of skeletal muscle and stabilizes Ca2+ transients when muscle fibres are subjected to osmotic shock injury (OSI). We show here that voltage-induced Ca2+ transients elicited in dysferlin-null A/J myofibres were smaller than control A/WySnJ fibres. Regional expression of Venus-dysferlin chimeras in A/J fibres restored the full amplitude of the Ca2+ transients and protected against OSI. We also show that drugs that target ryanodine receptors (RyR1: dantrolene, tetracaine, S107) and L-type Ca2+ channels (LTCCs: nifedipine, verapamil, diltiazem) prevented the decrease in Ca2+ transients in A/J fibres following OSI. Diltiazem specifically increased transients by ∼20% in uninjured A/J fibres, restoring them to control values. The fact that both RyR1s and LTCCs were involved in OSI-induced damage suggests that damage is mediated by increased Ca2+ leak from the sarcoplasmic reticulum (SR) through the RyR1. Congruent with this, injured A/J fibres produced Ca2+ sparks and Ca2+ waves. S107 (a stabilizer of RyR1-FK506 binding protein coupling that reduces Ca2+ leak) or local expression of Venus-dysferlin prevented OSI-induced Ca2+ waves. Our data suggest that dysferlin modulates SR Ca2+ release in skeletal muscle, and that in its absence OSI causes increased RyR1-mediated Ca2+ leak from the SR into the cytoplasm. Copyright 2017 The Authors.en_US
dc.description.sponsorshipThis research was supported by grants from the Jain Foundation, the Kahlert Foundation, the NIH (RO1 AR 064268), and the Muscular Dystrophy Association (no. 218313).en_US
dc.description.urihttps://doi.org/10.1113/JP274515en_US
dc.language.isoen_USen_US
dc.publisherBlackwell Publishing Ltden_US
dc.relation.ispartofJournal of Physiology
dc.subjectdysferlinen_US
dc.subjectexcitation-contraction couplingen_US
dc.subjectskeletal muscleen_US
dc.titleCoupling of excitation to Ca2+ release is modulated by dysferlinen_US
dc.typeArticleen_US
dc.identifier.doi10.1113/JP274515
dc.identifier.pmid28568606


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