Normal myoblast fusion requires myoferlin
Author:
Doherty Katherine R.1, Cave Andrew2, Davis Dawn Belt2, Delmonte Anthony J.2, Posey Avery2, Earley Judy U.2, Hadhazy Michele2, McNally Elizabeth M.23
Affiliation:
1. Department of Molecular Genetics and Cell Biology, The University of Chicago,Chicago, IL 60637, USA 2. Department of Medicine, The University of Chicago, Chicago, IL 60637,USA 3. Department of Human Genetics, The University of Chicago, Chicago, IL 60637,USA
Abstract
Muscle growth occurs during embryonic development and continues in adult life as regeneration. During embryonic muscle growth and regeneration in mature muscle, singly nucleated myoblasts fuse to each other to form myotubes. In muscle growth, singly nucleated myoblasts can also fuse to existing large,syncytial myofibers as a mechanism of increasing muscle mass without increasing myofiber number. Myoblast fusion requires the alignment and fusion of two apposed lipid bilayers. The repair of muscle plasma membrane disruptions also relies on the fusion of two apposed lipid bilayers. The protein dysferlin, the product of the Limb Girdle Muscular Dystrophy type 2 locus, has been shown to be necessary for efficient, calcium-sensitive,membrane resealing. We now show that the related protein myoferlin is highly expressed in myoblasts undergoing fusion, and is expressed at the site of myoblasts fusing to myotubes. Like dysferlin, we found that myoferlin binds phospholipids in a calcium-sensitive manner that requires the first C2A domain. We generated mice with a null allele of myoferlin. Myoferlin null myoblasts undergo initial fusion events, but they form large myotubes less efficiently in vitro, consistent with a defect in a later stage of myogenesis. In vivo, myoferlin null mice have smaller muscles than controls do, and myoferlin null muscle lacks large diameter myofibers. Additionally, myoferlin null muscle does not regenerate as well as wild-type muscle does, and instead displays a dystrophic phenotype. These data support a role for myoferlin in the maturation of myotubes and the formation of large myotubes that arise from the fusion of myoblasts to multinucleate myotubes.
Publisher
The Company of Biologists
Subject
Developmental Biology,Molecular Biology
Reference62 articles.
1. Antonio, J. and Gonyea, W. J. (1993). Skeletal muscle fiber hyperplasia. Med. Sci. Sports Exerc.25,1333-1345. 2. Bai, J., Wang, P. and Chapman, E. R. (2002). C2A activates a cryptic Ca(2+)-triggered membrane penetration activity within the C2B domain of synaptotagmin I. Proc. Natl. Acad. Sci. USA99,1665-1670. 3. Bansal, D., Miyake, K., Vogel, S. S., Groh, S., Chen, C. C.,Williamson, R., McNeil, P. L. and Campbell, K. P. (2003). Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature423,168-172. 4. Bashir, R., Britton, S., Strachan, T., Keers, S., Vafiadaki, E.,Lako, M., Richard, I., Marchand, S., Bourg, N., Argov, Z. et al.(1998). A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat. Genet.20,37-42. 5. Bornemann, A. and Schmalbruch, H. (1994). Immunocytochemistry of M-cadherin in mature and regenerating rat muscle. Anat. Rec.239,119-125.
Cited by
172 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|