{"doi":"10.1172/jci128190","title":"Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy","abstract":"Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been suggested as playing a role in the development of cardiac disease in the mdx mouse model of Duchenne muscular dystrophy (DMD); however, a mechanistic understanding of this association is lacking. Here, we identified a reduction of phosphorylation of Cx43 serines S325/S328/S330 in human and mouse DMD hearts. We hypothesized that hypophosphorylation of Cx43 serine-triplet triggers pathological Cx43 redistribution to the lateral sides of cardiomyocytes (remodeling). Therefore, we generated knockin mdx mice in which the Cx43 serine-triplet was replaced with either phospho-mimicking glutamic acids (mdxS3E) or nonphosphorylatable alanines (mdxS3A). The mdxS3E, but not mdxS3A, mice were resistant to Cx43 remodeling, with a corresponding reduction of Cx43 hemichannel activity. MdxS3E cardiomyocytes displayed improved intracellular Ca2+ signaling and a reduction of NADPH oxidase 2 (NOX2)/ROS production. Furthermore, mdxS3E mice were protected against inducible arrhythmias, related lethality, and the development of cardiomyopathy. Inhibition of microtubule polymerization by colchicine reduced both NOX2/ROS and oxidized CaMKII, increased S325/S328/S330 phosphorylation, and prevented Cx43 remodeling in mdx hearts. Together, these results demonstrate a mechanism of dystrophic Cx43 remodeling and suggest that targeting Cx43 may be a therapeutic strategy for preventing heart dysfunction and arrhythmias in DMD patients.","journal":"Journal of Clinical Investigation","year":2020,"id":57240,"datarank":0.6573039952010823,"base_score":4.382026634673881,"endowment":4.382026634673881,"self_citation_contribution":0.6573039952010823,"citation_network_contribution":0.0,"self_endowment_contribution":0.6573039952010823,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":79,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":298609,"name":"Mauricio A. Lillo","orcid":"0000-0002-2823-6619","position":1,"is_corresponding":false},{"id":298610,"name":"Julie Nouet","orcid":"0000-0002-6140-1604","position":2,"is_corresponding":false},{"id":300227,"name":"J. Patrick Gonzalez","orcid":null,"position":3,"is_corresponding":false},{"id":298611,"name":"Qingshi Zhao","orcid":"0009-0001-1015-2337","position":4,"is_corresponding":false},{"id":298612,"name":"Lai‐Hua Xie","orcid":"0000-0003-2600-2269","position":5,"is_corresponding":false},{"id":298613,"name":"Hong Li","orcid":"0000-0001-5731-5335","position":6,"is_corresponding":false},{"id":298614,"name":"Tong Liu","orcid":"0000-0002-1389-7051","position":7,"is_corresponding":false},{"id":298615,"name":"Xander H.T. Wehrens","orcid":"0000-0001-5044-672X","position":8,"is_corresponding":false},{"id":298616,"name":"Paul D. Lampe","orcid":"0000-0002-1399-2761","position":9,"is_corresponding":false},{"id":298617,"name":"Glenn I. Fishman","orcid":"0000-0002-2366-8527","position":10,"is_corresponding":false},{"id":298618,"name":"Natalia Shirokova","orcid":"0000-0003-4648-4592","position":11,"is_corresponding":false},{"id":298619,"name":"Jorge E. Contreras","orcid":"0000-0001-9203-1602","position":12,"is_corresponding":false},{"id":298620,"name":"Diego Fraidenraich","orcid":"0000-0001-5369-4446","position":13,"is_corresponding":false},{"id":300226,"name":"Eric Himelman","orcid":null,"position":0,"is_corresponding":true}],"reference_count":97,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T21:06:31.136481Z","pmid":"31910160","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}