Abstract
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-Δ43 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 (∼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-Δ43. The equilibrium constant for the cross-bridge force generation step was smallest in Tg-Δ43. 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.
| Original language | English |
|---|---|
| Pages (from-to) | 4394-4405 |
| Number of pages | 12 |
| Journal | FASEB Journal |
| Volume | 25 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2011 |
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Keywords
- Cross-bridge kinetics
- FHC-linked ELC mutation
- Myofilament lattice spacing
- Transgenic mice
ASJC Scopus subject areas
- Biochemistry
- Biotechnology
- Genetics
- Molecular Biology
Cite this
Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction. / Muthu, Priya; Wang, Li; Yuan, Chen Ching; Kazmierczak, Katarzyna; Huang, Wenrui; Hernandez, Olga M.; Kawai, Masataka; Irving, Thomas C.; Szczesna-Cordary, Danuta.
In: FASEB Journal, Vol. 25, No. 12, 01.12.2011, p. 4394-4405.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction
AU - Muthu, Priya
AU - Wang, Li
AU - Yuan, Chen Ching
AU - Kazmierczak, Katarzyna
AU - Huang, Wenrui
AU - Hernandez, Olga M.
AU - Kawai, Masataka
AU - Irving, Thomas C.
AU - Szczesna-Cordary, Danuta
PY - 2011/12/1
Y1 - 2011/12/1
N2 - 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-Δ43 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 (∼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-Δ43. The equilibrium constant for the cross-bridge force generation step was smallest in Tg-Δ43. 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.
AB - 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-Δ43 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 (∼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-Δ43. The equilibrium constant for the cross-bridge force generation step was smallest in Tg-Δ43. 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.
KW - Cross-bridge kinetics
KW - FHC-linked ELC mutation
KW - Myofilament lattice spacing
KW - Transgenic mice
UR - http://www.scopus.com/inward/record.url?scp=82655171630&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=82655171630&partnerID=8YFLogxK
U2 - 10.1096/fj.11-191973
DO - 10.1096/fj.11-191973
M3 - Article
C2 - 21885653
AN - SCOPUS:82655171630
VL - 25
SP - 4394
EP - 4405
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 12
ER -