期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 165, 期 -, 页码 103-114出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2022.01.002
关键词
Diastolic stiffness; Contractile function; Myofilament function; titin's C-zone; Heart disease
资金
- National Institutes of Health [R35HL144998]
- American Heart Association [19CDA34660099]
- Novel Research Project Awards in the area of Cardiovas-cular Disease and Medicine, Sarver Heart Center
- University of Arizona
This study reveals the importance of titin's C-zone in regulating cardiac function, as it affects the contraction and relaxation of cardiomyocytes by regulating the length of the thick filament.
Titin's C-zone is an inextensible segment in titin, comprised of 11 super-repeats and located in the cMyBP-Ccontaining region of the thick filament. Previously we showed that deletion of titin's super-repeats C1 and C2 (Ttn(delta C1-2) model) results in shorter thick filaments and contractile dysfunction of the left ventricular (LV) chamber but that unexpectedly LV diastolic stiffness is normal. Here we studied the contraction-relaxation kinetics from the time-varying elastance of the LV and intact cardiomyocyte, cellular work loops of intact cardiomyocytes, Ca2+ transients, cross-bridge kinetics, and myofilament Ca2+ sensitivity. Intact cardiomyocytes of Ttn(delta C1-2) mice exhibit systolic dysfunction and impaired relaxation. The time-varying elastance at both LV and single-cell levels showed that activation kinetics are normal in Ttn(delta C1-2) mice, but that relaxation is slower. The slowed relaxation is, in part, attributable to an increased myofilament Ca2+ sensitivity and slower early Ca2+ reuptake. Cross-bridge dynamics showed that cross-bridge kinetics are normal but that the number of force generating cross-bridges is reduced. In vivo sarcomere length (SL) measurements revealed that in Ttn(delta C1-2) mice the operating SL range of the LV is shifted towards shorter lengths. This normalizes the apparent cell and LV diastolic stiffness but further reduces systolic force as systole occurs further down on the ascending limb of the force-SL relation. We propose that the reduced working SLs reflect titin's role in regulating diastolic stiffness by altering the number of sarcomeres in series. Overall, our study reveals that thick filament length regulation by titin's C-zone is critical for normal cardiac function.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据