Abstract
Transgenic (Tg) mice expressing ∼95% of the 166V (aspartic acid to valine) mutation in the ventricular myosin regulatory light chain (RLC) shown to cause a malignant familial hypertrophic cardiomyopathy (FHC) phenotype were generated, and the skinned and intact papillary muscle fibers from the Tg-D166V mice were examined using a Guth muscle research system. A large increase in the Ca2+ sensitivity of force and ATPase (Delta;pCa50>0.25) and a significant decrease in maximal force and ATPase were observed in skinned muscle fibers from Tg-D166V mice compared with control mice. The cross-bridge dissociation rate g was dramatically decreased, whereas the energy cost (ATPase/force) was slightly increased in Tg-D166V fibers compared with controls. The calculated average force per D166V cross-bridge was also reduced. Intact papillary muscle data demonstrated prolonged force transients with no change in calcium transients in Tg-D166V fibers compared with control fibers. Histopathological examination revealed fibrotic lesions in the hearts of the older D166V mice. Our results suggest that a charge effect of the D166V mutation and/or a mutation-dependent decrease in RLC phosphorylation could initiate the slower kinetics of the D166V cross-bridges and ultimately affect the regulation of cardiac muscle contraction. Profound cellular changes observed in Tg-D166V myocardium when placed in vivo could trigger a series of pathological responses and result in poor prognosis for D166V-positive patients.-Kerrick, W. G. L., Kazmierczak, K., Xu, Y., Wang, Y., Szczesna-Cordary, D. Malignant familial hypertrophic cardiomyopathy D166V mutation in the ventricular myosin regulatory light chain causes profound effects in skinned and intact papillary muscle fibers from transgenic mice.
| Original language | English |
|---|---|
| Pages (from-to) | 855-865 |
| Number of pages | 11 |
| Journal | FASEB Journal |
| Volume | 23 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2009 |
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Keywords
- ATPase-pCa dependence
- Calcium and force transients
- Cross-bridge dissociation rate
- Energy cost
- Phosphorylation
ASJC Scopus subject areas
- Biochemistry
- Biotechnology
- Genetics
- Molecular Biology
Cite this
Malignant familial hypertrophic cardiomyopathy D166V mutation in the ventricular myosin regulatory light chain causes profound effects in skinned and intact papillary muscle fibers from transgenic mice. / Kerrick, W. Glenn; Kazmierczak, Katarzyna; Xu, Yuanyuan; Wang, Yingcai; Szczesna-Cordary, Danuta.
In: FASEB Journal, Vol. 23, No. 3, 01.03.2009, p. 855-865.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Malignant familial hypertrophic cardiomyopathy D166V mutation in the ventricular myosin regulatory light chain causes profound effects in skinned and intact papillary muscle fibers from transgenic mice
AU - Kerrick, W. Glenn
AU - Kazmierczak, Katarzyna
AU - Xu, Yuanyuan
AU - Wang, Yingcai
AU - Szczesna-Cordary, Danuta
PY - 2009/3/1
Y1 - 2009/3/1
N2 - Transgenic (Tg) mice expressing ∼95% of the 166V (aspartic acid to valine) mutation in the ventricular myosin regulatory light chain (RLC) shown to cause a malignant familial hypertrophic cardiomyopathy (FHC) phenotype were generated, and the skinned and intact papillary muscle fibers from the Tg-D166V mice were examined using a Guth muscle research system. A large increase in the Ca2+ sensitivity of force and ATPase (Delta;pCa50>0.25) and a significant decrease in maximal force and ATPase were observed in skinned muscle fibers from Tg-D166V mice compared with control mice. The cross-bridge dissociation rate g was dramatically decreased, whereas the energy cost (ATPase/force) was slightly increased in Tg-D166V fibers compared with controls. The calculated average force per D166V cross-bridge was also reduced. Intact papillary muscle data demonstrated prolonged force transients with no change in calcium transients in Tg-D166V fibers compared with control fibers. Histopathological examination revealed fibrotic lesions in the hearts of the older D166V mice. Our results suggest that a charge effect of the D166V mutation and/or a mutation-dependent decrease in RLC phosphorylation could initiate the slower kinetics of the D166V cross-bridges and ultimately affect the regulation of cardiac muscle contraction. Profound cellular changes observed in Tg-D166V myocardium when placed in vivo could trigger a series of pathological responses and result in poor prognosis for D166V-positive patients.-Kerrick, W. G. L., Kazmierczak, K., Xu, Y., Wang, Y., Szczesna-Cordary, D. Malignant familial hypertrophic cardiomyopathy D166V mutation in the ventricular myosin regulatory light chain causes profound effects in skinned and intact papillary muscle fibers from transgenic mice.
AB - Transgenic (Tg) mice expressing ∼95% of the 166V (aspartic acid to valine) mutation in the ventricular myosin regulatory light chain (RLC) shown to cause a malignant familial hypertrophic cardiomyopathy (FHC) phenotype were generated, and the skinned and intact papillary muscle fibers from the Tg-D166V mice were examined using a Guth muscle research system. A large increase in the Ca2+ sensitivity of force and ATPase (Delta;pCa50>0.25) and a significant decrease in maximal force and ATPase were observed in skinned muscle fibers from Tg-D166V mice compared with control mice. The cross-bridge dissociation rate g was dramatically decreased, whereas the energy cost (ATPase/force) was slightly increased in Tg-D166V fibers compared with controls. The calculated average force per D166V cross-bridge was also reduced. Intact papillary muscle data demonstrated prolonged force transients with no change in calcium transients in Tg-D166V fibers compared with control fibers. Histopathological examination revealed fibrotic lesions in the hearts of the older D166V mice. Our results suggest that a charge effect of the D166V mutation and/or a mutation-dependent decrease in RLC phosphorylation could initiate the slower kinetics of the D166V cross-bridges and ultimately affect the regulation of cardiac muscle contraction. Profound cellular changes observed in Tg-D166V myocardium when placed in vivo could trigger a series of pathological responses and result in poor prognosis for D166V-positive patients.-Kerrick, W. G. L., Kazmierczak, K., Xu, Y., Wang, Y., Szczesna-Cordary, D. Malignant familial hypertrophic cardiomyopathy D166V mutation in the ventricular myosin regulatory light chain causes profound effects in skinned and intact papillary muscle fibers from transgenic mice.
KW - ATPase-pCa dependence
KW - Calcium and force transients
KW - Cross-bridge dissociation rate
KW - Energy cost
KW - Phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=61449250645&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=61449250645&partnerID=8YFLogxK
U2 - 10.1096/fj.08-118182
DO - 10.1096/fj.08-118182
M3 - Article
C2 - 18987303
AN - SCOPUS:61449250645
VL - 23
SP - 855
EP - 865
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 3
ER -