Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells
Author
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González Jamett, Arlek M.
Author
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Báez Matus, Ximena
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Olivares, María José
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Hinostroza, Fernando
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Guerra Fernández, María José
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Vásquez Navarrete, Jacqueline
Author
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Bui, Mai Thao
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Guicheney, Pascale
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Romero, Norma
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Bevilacqua, Jorge
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Bitoun, Marc
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Caviedes Fernández, Pablo
Author
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Cárdenas, Ana María
Admission date
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2018-05-10T12:31:51Z
Available date
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2018-05-10T12:31:51Z
Publication date
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2017
Cita de ítem
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Scientific Reports Vol. 7: 4580
es_ES
Identifier
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10.1038/s41598-017-04418-w
Identifier
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https://repositorio.uchile.cl/handle/2250/147614
Abstract
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Dynamin-2 is a ubiquitously expressed GTP-ase that mediates membrane remodeling. Recent findings indicate that dynamin-2 also regulates actin dynamics. Mutations in dynamin-2 cause dominant centronuclear myopathy (CNM), a congenital myopathy characterized by progressive weakness and atrophy of skeletal muscles. However, the muscle-specific roles of dynamin-2 affected by these mutations remain elusive. Here we show that, in muscle cells, the GTP-ase activity of dynamin-2 is involved in de novo actin polymerization as well as in actin-mediated trafficking of the glucose transporter GLUT4. Expression of dynamin-2 constructs carrying CNM-linked mutations disrupted the formation of new actin filaments as well as the stimulus-induced translocation of GLUT4 to the plasma membrane. Similarly, mature muscle fibers isolated from heterozygous knock-in mice that harbor the dynamin-2 mutation p.R465W, an animal model of CNM, exhibited altered actin organization, reduced actin polymerization and impaired insulin-induced translocation of GLUT4 to the sarcolemma. Moreover, GLUT4 displayed aberrant perinuclear accumulation in biopsies from CNM patients carrying dynamin-2 mutations, further suggesting trafficking defects. These results suggest that dynamin-2 is a key regulator of actin dynamics and GLUT4 trafficking in muscle cells. Our findings also support a model in which impairment of actin-dependent trafficking contributes to the pathological mechanism in dynamin-2-associated CNM.
es_ES
Patrocinador
dc.description.sponsorship
Post-doctoral Fondecyt / CONICYT, 3160311 /
Fondecyt, 1160495 / Fondos ICM-ECONOMIA, P09-022-F /
Agence Nationale de la Recherche, France, ANR-14-CE12-0009 /
Millennium Scientific Initiative of the Ministerio de Economia, Fomento y Turismo /
Anillo, PIA, CONICYT, ACT-1121