TY - JOUR
T1 - Hypertrophic cardiomyopathy associated Lys104Glu mutation in the myosin regulatory light chain causes diastolic disturbance in mice
AU - Huang, Wenrui
AU - Liang, Jingsheng
AU - Kazmierczak, Katarzyna
AU - Muthu, Priya
AU - Duggal, Divya
AU - Farman, Gerrie P.
AU - Sorensen, Lars
AU - Pozios, Iraklis
AU - Abraham, Theodore P.
AU - Moore, Jeffrey R.
AU - Borejdo, Julian
AU - Szczesna-Cordary, Danuta
N1 - Funding Information:
This work was supported by the National Institutes of Health Grants R01 HL-071778 and HL-108343 (to DSC), HL-090786 (to JB and DSC), and HL-077280 (to JRM) and the American Heart Association Grant 12PRE12030412 (to WH).
PY - 2014/9
Y1 - 2014/9
N2 - We have examined, for the first time, the effects of the familial hypertrophic cardiomyopathy (HCM)-associated Lys104Glu mutation in the myosin regulatory light chain (RLC). Transgenic mice expressing the Lys104Glu substitution (Tg-MUT) were generated and the results were compared to Tg-WT (wild-type human ventricular RLC) mice. Echocardiography with pulse wave Doppler in 6. month-old Tg-MUT showed early signs of diastolic disturbance with significantly reduced E/A transmitral velocities ratio. Invasive hemodynamics in 6. month-old Tg-MUT mice also demonstrated a borderline significant prolonged isovolumic relaxation time (Tau) and a tendency for slower rate of pressure decline, suggesting alterations in diastolic function in Tg-MUT. Six month-old mutant animals had no LV hypertrophy; however, at >. 13. months they displayed significant hypertrophy and fibrosis. In skinned papillary muscles from 5 to 6. month-old mice a mutation induced reduction in maximal tension and slower muscle relaxation rates were observed. Mutated cross-bridges showed increased rates of binding to the thin filaments and a faster rate of the power stroke. In addition, ~. 2-fold lower level of RLC phosphorylation was observed in the mutant compared to Tg-WT. In line with the higher mitochondrial content seen in Tg-MUT hearts, the MUT-myosin ATPase activity was significantly higher than WT-myosin, indicating increased energy consumption. In the in vitro motility assay, MUT-myosin produced higher actin sliding velocity under zero load, but the velocity drastically decreased with applied load in the MUT vs. WT myosin. Our results suggest that diastolic disturbance (impaired muscle relaxation, lower E/A) and inefficiency of energy use (reduced contractile force and faster ATP consumption) may underlie the Lys104Glu-mediated HCM phenotype.
AB - We have examined, for the first time, the effects of the familial hypertrophic cardiomyopathy (HCM)-associated Lys104Glu mutation in the myosin regulatory light chain (RLC). Transgenic mice expressing the Lys104Glu substitution (Tg-MUT) were generated and the results were compared to Tg-WT (wild-type human ventricular RLC) mice. Echocardiography with pulse wave Doppler in 6. month-old Tg-MUT showed early signs of diastolic disturbance with significantly reduced E/A transmitral velocities ratio. Invasive hemodynamics in 6. month-old Tg-MUT mice also demonstrated a borderline significant prolonged isovolumic relaxation time (Tau) and a tendency for slower rate of pressure decline, suggesting alterations in diastolic function in Tg-MUT. Six month-old mutant animals had no LV hypertrophy; however, at >. 13. months they displayed significant hypertrophy and fibrosis. In skinned papillary muscles from 5 to 6. month-old mice a mutation induced reduction in maximal tension and slower muscle relaxation rates were observed. Mutated cross-bridges showed increased rates of binding to the thin filaments and a faster rate of the power stroke. In addition, ~. 2-fold lower level of RLC phosphorylation was observed in the mutant compared to Tg-WT. In line with the higher mitochondrial content seen in Tg-MUT hearts, the MUT-myosin ATPase activity was significantly higher than WT-myosin, indicating increased energy consumption. In the in vitro motility assay, MUT-myosin produced higher actin sliding velocity under zero load, but the velocity drastically decreased with applied load in the MUT vs. WT myosin. Our results suggest that diastolic disturbance (impaired muscle relaxation, lower E/A) and inefficiency of energy use (reduced contractile force and faster ATP consumption) may underlie the Lys104Glu-mediated HCM phenotype.
KW - Contractile force
KW - Echocardiography
KW - Hypertrophic cardiomyopathy (HCM)
KW - Mutation
KW - Myosin regulatory light chain
KW - Transgenic mice
UR - http://www.scopus.com/inward/record.url?scp=84904745693&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2014.06.011
DO - 10.1016/j.yjmcc.2014.06.011
M3 - Article
C2 - 24992035
AN - SCOPUS:84904745693
SN - 0022-2828
VL - 74
SP - 318
EP - 329
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -