Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Scientific Reports Year : 2017

Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells

Arlek M González-Jamett
  • Function : Author
Ximena Baez-Matus
  • Function : Author
María José Olivares
  • Function : Author
Fernando Hinostroza
  • Function : Author
Maria José Guerra-Fernández
  • Function : Author
Jacqueline Vasquez-Navarrete
  • Function : Author
Mai Thao Bui
  • Function : Author
Norma Beatriz Romero
  • Function : Author
Jorge A Bevilacqua
Marc Bitoun
  • Function : Author
Pablo Caviedes
  • Function : Author
  • PersonId : 844083
Ana M Cárdenas
  • Function : Author


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. Dynamins are mechano-chemical large GTP-ases, whose catalytic activity is required in several membrane-based processes including endocytosis, vesicle trafficking, and exocytosis 1-4. These proteins also exhibit a critical role in actin cytoskeleton dynamics by promoting elongation 5 , remodeling 6 and stabilizing actin filaments 7. Dynamins are composed of five conserved domains: an N-terminal GTP-ase domain, a middle structural domain, a pleckstrin homology (PH) domain that binds phosphoinositides, a GTP-ase effector domain (GED), and a C-terminal proline/arginine-rich domain (PRD) that binds SH3-domain-containing partners 1-4. Three dynamin isoforms have been described in mammals, which share approximately 80% of sequence homology
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Dates and versions

inserm-04021354 , version 1 (09-03-2023)



Arlek M González-Jamett, Ximena Baez-Matus, María José Olivares, Fernando Hinostroza, Maria José Guerra-Fernández, et al.. Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells. Scientific Reports, 2017, 7, ⟨10.1038/s41598-017-04418-w⟩. ⟨inserm-04021354⟩
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