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Disrupted myosin cross-bridge cycling kinetics triggers muscle weakness in nebulin-related myopathy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
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2011 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 25, no 6, 1903-1913 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2011. Vol. 25, no 6, 1903-1913 p.
Keyword [en]
congenital myopathy, tropomyosin activation
National Category
Physiology
Research subject
Clinical Neurophysiology
Identifiers
URN: urn:nbn:se:uu:diva-154673DOI: 10.1096/fj.10-176727ISI: 000291023800014PubMedID: 21350120OAI: oai:DiVA.org:uu-154673DiVA: diva2:421588
Available from: 2011-06-09 Created: 2011-06-09 Last updated: 2017-12-11Bibliographically approved

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