Journal
FASEB JOURNAL
Volume 23, Issue 3, Pages 855-865Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.08-118182
Keywords
phosphorylation; calcium and force transients; cross-bridge dissociation rate; energy cost; ATPase-pCa dependence
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Funding
- NIH [HL071778]
- American Heart Association [0555320B]
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Transgenic (Tg) mice expressing similar to 95% of the D166V (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 pCa(50)>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. FASEB J. 23, 855-865 (2009)
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