Journal
FASEB JOURNAL
Volume 25, Issue 12, Pages 4394-4405Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.11-191973
Keywords
cross-bridge kinetics; FHC-linked ELC mutation; myofilament lattice spacing; transgenic mice
Categories
Funding
- U.S. National Institutes of Health (NIH) [HL071778, HL090786, HL070041]
- American Heart Association [10POST3420009]
- U.S. DOE [AC02-06CH11357]
- NIH [RR-08630]
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The myosin essential light chain (ELC) is a structural component of the actomyosin cross-bridge, but its function is poorly understood, especially the role of the cardiac specific N-terminal extension in modulating actomyosin interaction. Here, we generated transgenic (Tg) mice expressing the A57G (alanine to glycine) mutation in the cardiac ELC known to cause familial hypertrophic cardiomyopathy (FHC). The function of the ELC N-terminal extension was investigated with the Tg-Delta 43 mouse model, whose myocardium expresses a truncated ELC. Low-angle X-ray diffraction studies on papillary muscle fibers in rigor revealed a decreased interfilament spacing (similar to 1.5 nm) and no alterations in cross-bridge mass distribution in Tg-A57G mice compared to Tg-WT, expressing the full-length nonmutated ELC. The truncation mutation showed a 1.3-fold increase in I(1,1)/I(1,0), indicating a shift of cross-bridge mass from the thick filament backbone toward the thin filaments. Mechanical studies demonstrated increased stiffness in Tg-A57G muscle fibers compared to Tg-WT or Tg-Delta 43. The equilibrium constant for the cross-bridge force generation step was smallest in Tg-Delta 43. These results support an important role for the N-terminal ELC extension in prepositioning the cross-bridge for optimal force production. Subtle changes in the ELC sequence were sufficient to alter cross-bridge properties and lead to pathological phenotypes.-Muthu, P., Wang, L., Yuan, C.-C., Kazmierczak, K., Huang, W., Hernandez, O. M., Kawai, M., Irving, T. C., Szczesna-Cordary, D. Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction. FASEB J. 25, 4394-4405 (2011). www.fasebj.org
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