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dc.contributor.authorFernández G.
dc.contributor.authorArias-Bravo G.
dc.contributor.authorBevilacqua J.A.
dc.contributor.authorCastillo-Ruiz M.
dc.contributor.authorCaviedes P.
dc.contributor.authorSáez J.C.
dc.contributor.authorCea L.A.
dc.date.accessioned2020-09-02T22:17:27Z
dc.date.available2020-09-02T22:17:27Z
dc.date.issued2020
dc.identifier10.1016/j.bbadis.2020.165800
dc.identifier.citation1866, 8, -
dc.identifier.issn09254439
dc.identifier.urihttps://hdl.handle.net/20.500.12728/4442
dc.descriptionDysferlinopathy is a genetic human disease caused by mutations in the gene that encodes the dysferlin protein (DYSF). Dysferlin is believed to play a relevant role in cell membrane repair. However, in dysferlin-deficient (blAJ) mice (a model of dysferlinopathies) the recovery of the membrane resealing function by means of the expression of a mini-dysferlin does not arrest progressive muscular damage, suggesting the participation of other unknown pathogenic mechanisms. Here, we show that proteins called connexins 39, 43 and 45 (Cx39, Cx43 and Cx45, respectively) are expressed by blAJ myofibers and form functional hemichannels (Cx HCs) in the sarcolemma. At rest, Cx HCs increased the sarcolemma permeability to small molecules and the intracellular Ca2+ signal. In addition, skeletal muscles of blAJ mice showed lipid accumulation and lack of dysferlin immunoreactivity. As sign of extensive damage and atrophy, muscles of blAJ mice presented elevated numbers of myofibers with internal nuclei, increased number of myofibers with reduced cross-sectional area and elevated creatine kinase activity in serum. In agreement with the extense muscle damage, mice also showed significantly low motor performance. We generated blAJ mice with myofibers deficient in Cx43 and Cx45 expression and found that all above muscle and systemic alterations were absent, indicating that these two Cxs play a critical role in a novel pathogenic mechanism of dysfernolophaties, which is discussed herein. Therefore, Cx HCs could constitute an attractive target for pharmacologic treatment of dyferlinopathies. © 2020 Elsevier B.V.
dc.language.isoen
dc.publisherElsevier B.V.
dc.subjectCalcium ion
dc.subjectFat infiltration
dc.subjectMembrane permeability
dc.subjectMuscular dystrophy
dc.subjectMuscular performance
dc.subjectconnexin 39
dc.subjectconnexin 43
dc.subjectconnexin 45
dc.subjectcreatine kinase
dc.subjectdysferlin
dc.subjectgap junction protein
dc.subjectmyogenin
dc.subjectunclassified drug
dc.subjectadult
dc.subjectanimal cell
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectanimal tissue
dc.subjectArticle
dc.subjectcalcium cell level
dc.subjectcalcium signaling
dc.subjectcell membrane permeability
dc.subjectcomparative study
dc.subjectconnective tissue
dc.subjectcontrolled study
dc.subjectcreatine kinase blood level
dc.subjectdysferlinopathy
dc.subjectenzyme activity
dc.subjectgastrocnemius muscle
dc.subjectgene mutation
dc.subjecthuman
dc.subjectimmunoreactivity
dc.subjectlipid storage
dc.subjectmale
dc.subjectmolecular pathology
dc.subjectmotor performance
dc.subjectmouse
dc.subjectmuscle atrophy
dc.subjectmuscle cell
dc.subjectmuscle function
dc.subjectmuscle injury
dc.subjectmuscle tissue
dc.subjectnonhuman
dc.subjectpriority journal
dc.subjectprotein expression
dc.subjectrotarod test
dc.subjectsarcolemma
dc.subjectskeletal muscle
dc.titleMyofibers deficient in connexins 43 and 45 expression protect mice from skeletal muscle and systemic dysfunction promoted by a dysferlin mutation
dc.typeArticle


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