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Mutations in the nebulin gene (\n                    <jats:italic>NEB<\/jats:italic>\n                    ) 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\u2010ray diffraction patterns of human membrane\u2010perme\u2010abilized 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\u2010actin interactions in the strong binding state. This phenomenon prevents complete thin\u2010filament activation, more especially proper and full tropomyosin movement, further limiting additional binding of myosin cross\u2010bridges. At the cell level, this reduces the force\u2010generating 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\u2010bridge cycling kinetics.\u2014Ochala, J., Lehtokari, V.\u2010L., Iwamoto, H., Li, M., Feng, H.\u2010Z., Jin, J. P., Yagi, N., Wallgren\u2010Pettersson, C. P\u00e9nisson\u2010Besnier, I., Larsson, L. Disrupted myosin cross\u2010bridge cycling kinetics triggers muscle weakness in nebulin\u2010related myopathy.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    25, 1903\u20101913 (2011).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.10-176727","type":"journal-article","created":{"date-parts":[[2011,2,24]],"date-time":"2011-02-24T22:47:06Z","timestamp":1298587626000},"page":"1903-1913","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Disrupted myosin cross\u2010bridge cycling kinetics triggers muscle weakness in nebulin\u2010related myopathy"],"prefix":"10.1096","volume":"25","author":[{"given":"Julien","family":"Ochala","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Clinical Neurophysiology Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vilma\u2010Lotta","family":"Lehtokari","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Folkha\u00a8lsan Institute of Genetics Haartman Institute University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Iwamoto","sequence":"additional","affiliation":[{"name":"Japan Synchrotron Radiation Research Institute Hyogo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meishan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Clinical Neurophysiology Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han\u2010Zhong","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Physiology Wayne State University School of Medicine Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian\u2010Ping","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Physiology Wayne State University School of Medicine Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Yagi","sequence":"additional","affiliation":[{"name":"Japan Synchrotron Radiation Research Institute Hyogo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Wallgren\u2010Pettersson","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Folkha\u00a8lsan Institute of Genetics Haartman Institute University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"P\u00e9nisson\u2010Besnier","sequence":"additional","affiliation":[{"name":"Centre de Reference des Maladies Neuromusculaires Departement de Neurologie Centre Hospitalier Universitaire d'Angers Angers France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Larsson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Clinical Neurophysiology Uppsala University Uppsala Sweden"},{"name":"Department of Biobehavioral Health Pennsylvania State University University Park Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,2,24]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0065-227X(96)81668-6"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.107.6.2199"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2008.10.053"},{"key":"e_1_2_6_5_1","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1083\/jcb.201001043","article-title":"Nebulin regulates actin filament lengths by a stabilization mechanism","volume":"189","author":"Pappas C. 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