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Disrupted myosin cross‐bridge cycling kinetics triggers muscle weakness in nebulin‐related myopathy
Author(s) -
Ochala Julien,
Lehtokari VilmaLotta,
Iwamoto Hiroyuki,
Li Meishan,
Feng HanZhong,
Jin JianPing,
Yagi Naoto,
WallgrenPettersson Carina,
PénissonBesnier Isabelle,
Larsson Lars
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-176727
Subject(s) - nebulin , myosin , actin , muscle weakness , tropomyosin , muscle contraction , nemaline myopathy , myopathy , weakness , skeletal muscle , myh7 , biology , microbiology and biotechnology , sarcomere , biophysics , myosin light chain kinase , myocyte , anatomy , titin , genetics
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‐perme‐abilized 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. Pénisson‐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