[PMID]: | 28467684 |
[Au] Autor: | Wang L; Kazmierczak K; Yuan CC; Yadav S; Kawai M; Szczesna-Cordary D |
[Ad] Endereço: | Departments of Anatomy and Cell Biology and Internal Medicine, University of Iowa, IA, USA. |
[Ti] Título: | Cardiac contractility, motor function, and cross-bridge kinetics in N47K-RLC mutant mice. |
[So] Source: | FEBS J;284(12):1897-1913, 2017 06. |
[Is] ISSN: | 1742-4658 |
[Cp] País de publicação: | England |
[La] Idioma: | eng |
[Ab] Resumo: | We have investigated the physiology and mechanical profiles of skinned papillary muscle fibers from transgenic mice expressing the N47K mutation in the myosin regulatory light chain (RLC), shown to cause hypertrophic cardiomyopathy in humans. The results were compared with wild-type (WT) mice, both expressing the human ventricular RLC. Rate constants of a cross-bridge (XB) cycle were deduced from tension transients induced by sinusoidal length changes during maximal Ca activation, and were studied as a function of MgATP, MgADP, and Pi concentrations. N47K mutant showed slower XB cycles but higher actin-activated ATPase activity compared with WT. Consequently, N47K exhibited larger tension than WT. K (ADP association constant) and K (equilibrium constant of force generation) were larger in N47K, and K (ATP association constant) was slightly larger in N47K vs. WT, demonstrating stronger nucleotide binding and force generation abilities of the mutant, but no changes in rigor acto-myosin binding were observed. Tension per XB was similar among groups, but N47K exhibited more XB distribution in the attached state. Larger values of tension and higher ATPase in N47K suggested that more cross-bridges participated in tension production in the mutant myocardium compared with WT. In vivo analysis of heart function, performed in ~ 12.5-month-old mice by echocardiography and invasive hemodynamics, demonstrated a significant decrease in dP/dt -end-diastolic volume relationship, indicating a depression of ventricular contractility in N47K mice. Our findings suggest that the N47K mutation exerts its action through direct alterations of myosin motor function that ultimately result in pathological hypertrophic remodeling in N47K hearts. |
[Mh] Termos MeSH primário: |
Atividade Motora/fisiologia Mutação Contração Miocárdica/fisiologia Cadeias Leves de Miosina/genética Músculos Papilares/fisiopatologia
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[Mh] Termos MeSH secundário: |
Actinas/metabolismo Difosfato de Adenosina/metabolismo Trifosfato de Adenosina/metabolismo Animais Cálcio/metabolismo Seres Humanos Cinética Camundongos Camundongos Transgênicos Cadeias Leves de Miosina/metabolismo Miosinas
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[Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Actins); 0 (Myosin Light Chains); 61D2G4IYVH (Adenosine Diphosphate); 8L70Q75FXE (Adenosine Triphosphate); EC 3.6.4.1 (Myosins); SY7Q814VUP (Calcium) |
[Em] Mês de entrada: | 1709 |
[Cu] Atualização por classe: | 180212 |
[Lr] Data última revisão:
| 180212 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170504 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1111/febs.14096 |
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