title: Disrupted myosin cross-bridge cycling kinetics triggers muscle weakness in nebulin-related myopathy.
abstract: 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.
authors.affiliation: Department of Neuroscience, Clinical Neurophysiology, Uppsala University Hospital, Entrance 85, 3rd floor, SE-751 85 Uppsala, Sweden. julien.ochala@neuro.uu.se
authors.forename: Julien
authors.initials: J
authors.lastname: Ochala
authors.forename: Vilma-Lotta
authors.initials: VL
authors.lastname: Lehtokari
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Iwamoto
authors.forename: Meishan
authors.initials: M
authors.lastname: Li
authors.forename: Han-Zhong
authors.initials: HZ
authors.lastname: Feng
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Jin
authors.forename: Naoto
authors.initials: N
authors.lastname: Yagi
authors.forename: Carina
authors.initials: C
authors.lastname: Wallgren-Pettersson
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pénisson-Besnier
authors.forename: Lars
authors.initials: L
authors.lastname: Larsson
mesh_terms: D000328:Adult; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018908:Muscle Weakness / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation; D017696:Myopathies, Nemaline / Q000235:genetics / Q000378:metabolism*; D009218:Myosins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D009124:Muscle Proteins; C035620:nebulin; D009218:Myosins