Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells
Abstract 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...
Enregistré dans:
| Auteurs principaux: | , , , , , , , , , , , , |
|---|---|
| Format: | article |
| Langue: | EN |
| Publié: |
Nature Portfolio
2017
|
| Sujets: | |
| Accès en ligne: | https://doaj.org/article/9c9e6b6e323144c598b2710c66121577 |
| Tags: |
Ajouter un tag
Pas de tags, Soyez le premier à ajouter un tag!
|
| id |
oai:doaj.org-article:9c9e6b6e323144c598b2710c66121577 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:9c9e6b6e323144c598b2710c661215772021-12-02T11:53:07ZDynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells10.1038/s41598-017-04418-w2045-2322https://doaj.org/article/9c9e6b6e323144c598b2710c661215772017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04418-whttps://doaj.org/toc/2045-2322Abstract 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.Arlek M. González-JamettXimena Baez-MatusMaría José OlivaresFernando HinostrozaMaria José Guerra-FernándezJacqueline Vasquez-NavarreteMai Thao BuiPascale GuicheneyNorma Beatriz RomeroJorge A. BevilacquaMarc BitounPablo CaviedesAna M. CárdenasNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Arlek M. González-Jamett Ximena Baez-Matus María José Olivares Fernando Hinostroza Maria José Guerra-Fernández Jacqueline Vasquez-Navarrete Mai Thao Bui Pascale Guicheney Norma Beatriz Romero Jorge A. Bevilacqua Marc Bitoun Pablo Caviedes Ana M. Cárdenas Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells |
| description |
Abstract 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. |
| format |
article |
| author |
Arlek M. González-Jamett Ximena Baez-Matus María José Olivares Fernando Hinostroza Maria José Guerra-Fernández Jacqueline Vasquez-Navarrete Mai Thao Bui Pascale Guicheney Norma Beatriz Romero Jorge A. Bevilacqua Marc Bitoun Pablo Caviedes Ana M. Cárdenas |
| author_facet |
Arlek M. González-Jamett Ximena Baez-Matus María José Olivares Fernando Hinostroza Maria José Guerra-Fernández Jacqueline Vasquez-Navarrete Mai Thao Bui Pascale Guicheney Norma Beatriz Romero Jorge A. Bevilacqua Marc Bitoun Pablo Caviedes Ana M. Cárdenas |
| author_sort |
Arlek M. González-Jamett |
| title |
Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells |
| title_short |
Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells |
| title_full |
Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells |
| title_fullStr |
Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells |
| title_full_unstemmed |
Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells |
| title_sort |
dynamin-2 mutations linked to centronuclear myopathy impair actin-dependent trafficking in muscle cells |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/9c9e6b6e323144c598b2710c66121577 |
| work_keys_str_mv |
AT arlekmgonzalezjamett dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT ximenabaezmatus dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT mariajoseolivares dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT fernandohinostroza dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT mariajoseguerrafernandez dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT jacquelinevasqueznavarrete dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT maithaobui dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT pascaleguicheney dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT normabeatrizromero dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT jorgeabevilacqua dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT marcbitoun dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT pablocaviedes dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells AT anamcardenas dynamin2mutationslinkedtocentronuclearmyopathyimpairactindependenttraffickinginmusclecells |
| _version_ |
1718394881981808640 |