Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells
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 skele...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; ; |
|---|---|
| Format: | Article |
| Status: | Published version |
| Publication date: | 2017 |
| Country: | Chile |
| Institution: | Agencia Nacional de Investigación y Desarrollo |
| Repository: | Articulos_ANID |
| Language: | English |
| OAI Identifier: | oai:repositorio.anid.cl:10533/251894 |
| Online Access: | https://hdl.handle.net/10533/251894 |
| Access Level: | Open access |
| Keyword: | Ciencias Naturales Ciencias Biológicas Biología General |
| Summary: | 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. Keywords. KeyWords Plus:GLUCOSE-TRANSPORTER GLUT4; SKELETAL-MUSCLE; GTPASE DYNAMIN; MEMBRANE TRAFFICKING; INSULIN-RESISTANCE; BINDING PROTEIN; GAMMA-ACTIN; ENDOCYTOSIS; MICE; TRANSLOCATION |
|---|