{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:06:41Z","timestamp":1790474801369,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,8,21]],"date-time":"2020-08-21T00:00:00Z","timestamp":1597968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["11160739"],"award-info":[{"award-number":["11160739"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1191329"],"award-info":[{"award-number":["1191329"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ICM-Econom\u00eda","award":["P09-022-F"],"award-info":[{"award-number":["P09-022-F"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dysferlinopathies are muscle dystrophies caused by mutations in the gene encoding dysferlin, a relevant protein for membrane repair and trafficking. These diseases are untreatable, possibly due to the poor knowledge of relevant molecular targets. Previously, we have shown that human myofibers from patient biopsies as well as myotubes derived from immortalized human myoblasts carrying a mutated form of dysferlin express connexin proteins, but their relevance in myoblasts fate and function remained unknown. In the present work, we found that numerous myoblasts bearing a mutated dysferlin when induced to acquire myogenic commitment express PPAR\u03b3, revealing adipogenic instead of myogenic commitment. These cell cultures presented many mononucleated cells with fat accumulation and within 48 h of differentiation formed fewer multinucleated cells. In contrast, dysferlin deficient myoblasts treated with boldine, a connexin hemichannels blocker, neither expressed PPAR\u03b3, nor accumulated fat and formed similar amount of multinucleated cells as wild type precursor cells. We recently demonstrated that myofibers of skeletal muscles from blAJ mice (an animal model of dysferlinopathies) express three connexins (Cx39, Cx43, and Cx45) that form functional hemichannels (HCs) in the sarcolemma. In symptomatic blAJ mice, we now show that eight-week treatment with a daily dose of boldine showed a progressive recovery of motor activity reaching normality. At the end of this treatment, skeletal muscles were comparable to those of wild type mice and presented normal CK activity in serum. Myofibers of boldine-treated blAJ mice also showed strong dysferlin-like immunoreactivity. These findings reveal that muscle dysfunction results from a pathophysiologic mechanism triggered by mutated dysferlin and downstream connexin hemichannels expressed de novo lead to a drastic reduction of myogenesis and favor muscle damage. Thus, boldine could represent a therapeutic opportunity to treat dysfernilopathies.<\/jats:p>","DOI":"10.3390\/ijms21176025","type":"journal-article","created":{"date-parts":[[2020,8,21]],"date-time":"2020-08-21T09:21:51Z","timestamp":1598001711000},"page":"6025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Blockade of Hemichannels Normalizes the Differentiation Fate of Myoblasts and Features of Skeletal Muscles from Dysferlin-Deficient Mice"],"prefix":"10.3390","volume":"21","author":[{"given":"Luis A.","family":"Cea","sequence":"first","affiliation":[{"name":"Instituto de Ciencias Biom\u00e9dicas, Facultad de Ciencias de la Salud, Universidad Aut\u00f3noma de Chile, Santiago 8910060, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Instituto de Ciencias Biom\u00e9dicas, Facultad de Ciencias de la Salud, Universidad Aut\u00f3noma de Chile, Santiago 8910060, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guisselle","family":"Arias-Bravo","sequence":"additional","affiliation":[{"name":"Instituto de Ciencias Biom\u00e9dicas, Facultad de Ciencias de la Salud, Universidad Aut\u00f3noma de Chile, Santiago 8910060, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0005-408X","authenticated-orcid":false,"given":"Mario","family":"Castillo-Ruiz","sequence":"additional","affiliation":[{"name":"Escuela de Qu\u00edmica y Farmacia, Facultad de Medicina, Universidad Andres Bello, Santiago 8370149, Chile"},{"name":"Departamento de Ciencias Qu\u00edmicas y Biol\u00f3gicas, Facultad de Ciencias de la Salud, Universidad Bernardo O Higgins, Santiago 8370854, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4491-3907","authenticated-orcid":false,"given":"Rosalba","family":"Escamilla","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valpara\u00edso, Universidad de Valpara\u00edso, Valpara\u00edso 2340000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda C.","family":"Bra\u00f1es","sequence":"additional","affiliation":[{"name":"Consorcio de Investigaci\u00f3n Naturalis SA, Santiago 8700000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan C.","family":"S\u00e1ez","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias, Centro Interdisciplinario de Neurociencias de Valpara\u00edso, Universidad de Valpara\u00edso, Valpara\u00edso 2340000, Chile"},{"name":"Departamento de Fisiolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8320000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nature01573","article-title":"Defective membrane repair in dysferlin-deficient muscular dystrophy","volume":"423","author":"Bansal","year":"2003","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lostal, W., Bartoli, M., Roudaut, C., Bourg, N., Krahn, M., Pryadkina, M., Borel, P., Suel, L., Roche, J.A., and Stockholm, D. 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