Disrupted myosin cross-bridge cycling kinetics triggers muscle weakness in nebulin-related myopathy
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Disrupted myosin cross-bridge cycling kinetics triggers muscle weakness in nebulin-related myopathy. / Ochala, Julien; Lehtokari, Vilma Lotta; Iwamoto, Hiroyuki; Li, Meishan; Feng, Han Zhong; Jin, Jian Ping; Yagi, Naoto; Wallgren-Pettersson, Carina; Pénisson-Besnier, Isabelle; Larsson, Lars.
In: FASEB Journal, Vol. 25, No. 6, 06.2011, p. 1903-1913.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Disrupted myosin cross-bridge cycling kinetics triggers muscle weakness in nebulin-related myopathy
AU - Ochala, Julien
AU - Lehtokari, Vilma Lotta
AU - Iwamoto, Hiroyuki
AU - Li, Meishan
AU - Feng, Han Zhong
AU - Jin, Jian Ping
AU - Yagi, Naoto
AU - Wallgren-Pettersson, Carina
AU - Pénisson-Besnier, Isabelle
AU - Larsson, Lars
PY - 2011/6
Y1 - 2011/6
N2 - 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.
AB - 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.
KW - Congenital myopathy
KW - Tropomyosin activation
UR - http://www.scopus.com/inward/record.url?scp=79957918034&partnerID=8YFLogxK
U2 - 10.1096/fj.10-176727
DO - 10.1096/fj.10-176727
M3 - Journal article
C2 - 21350120
AN - SCOPUS:79957918034
VL - 25
SP - 1903
EP - 1913
JO - F A S E B Journal
JF - F A S E B Journal
SN - 0892-6638
IS - 6
ER -
ID: 245664534