Journal
FASEB JOURNAL
Volume 25, Issue 6, Pages 1903-1913Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.10-176727
Keywords
congenital myopathy; tropomyosin activation
Categories
Funding
- Swedish Research Council [8651]
- Association Francaise contre les Myopathies
- Tore Nilson Stiftelse
- Stiftelsen Apotekare Hedbergs Fond for Medicinsk Forskning
- Rektors Resebidrag fran Wallenbergstiftelsen
- U.S. National Institutes of Health [AR-048816]
- Academy of Finland
- Sigrid Juselius Foundation
- Finska Lakaresallskapet
- Medicinska Understodsforeningen Liv och Halsa
- Swedish Cancer Foundation
- European Commission [CT-223756]
- King Gustaf V and Queen Victoria's Foundation
- Thureus Foundation
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Nebulin is a giant protein expressed at high levels in skeletal muscle. Mutations in the nebulin gene (NEB) lead to muscle weakness and various congenital myopathies. Despite increasing clinical and scientific interest, the pathogenesis of weakness remains unknown. The present study, therefore, aims at unraveling the underlying molecular mechanisms. Hence, we recorded and analyzed the mechanics as well as the X-ray diffraction patterns of human membrane-permeabilized single muscle fibers expressing nebulin mutations. Results demonstrated that, during contraction, the cycling rate of myosin heads attaching to actin is dramatically perturbed, causing a reduction in the fraction of myosin-actin interactions in the strong binding state. This phenomenon prevents complete thin-filament activation, more especially proper and full tropomyosin movement, further limiting additional binding of myosin cross-bridges. At the cell level, this reduces the force-generating capacity and, overall, provokes muscle weakness. To reverse such a negative cascade of events, future potential therapeutic interventions should, therefore, focus on the triggering component, the altered myosin cross-bridge cycling kinetics.-Ochala, J., Lehtokari, V.-L., Iwamoto, H., Li, M., Feng, H.-Z., Jin, J. P., Yagi, N., Wallgren-Pettersson, C. Penisson-Besnier, I., Larsson, L. Disrupted myosin cross-bridge cycling kinetics triggers muscle weakness in nebulin-related myopathy. FASEB J. 25, 1903-1913 (2011). www.fasebj.org
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