Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
J Gen Physiol. 2023 Jun 5;155(6). doi: 10.1085/jgp.202213288. Epub 2023 Apr 27.
Cardiac hypertrophy is associated with diastolic heart failure (DHF), a syndrome in which systolic function is preserved but cardiac filling dynamics are depressed. The molecular mechanisms underlying DHF and the potential role of altered cross-bridge cycling are poorly understood. Accordingly, chronic pressure overload was induced by surgically banding the thoracic ascending aorta (AOB) in ∼400 g female Dunkin Hartley guinea pigs (AOB); Sham-operated age-matched animals served as controls. Guinea pigs were chosen to avoid the confounding impacts of altered myosin heavy chain (MHC) isoform expression seen in other small rodent models. In vivo cardiac function was assessed by echocardiography; cardiac hypertrophy was confirmed by morphometric analysis. AOB resulted in left ventricle (LV) hypertrophy and compromised diastolic function with normal systolic function. Biochemical analysis revealed exclusive expression of β-MHC isoform in both sham control and AOB LVs. Myofilament function was assessed in skinned multicellular preparations, skinned single myocyte fragments, and single myofibrils prepared from frozen (liquid N2) LVs. The rates of force-dependent ATP consumption (tension-cost) and force redevelopment (Ktr), as well as myofibril relaxation time (Timelin) were significantly blunted in AOB, indicating reduced cross-bridge cycling kinetics. Maximum Ca2+ activated force development was significantly reduced in AOB myocytes, while no change in myofilament Ca2+ sensitivity was observed. Our results indicate blunted cross-bridge cycle in a β-MHC small animal DHF model. Reduced cross-bridge cycling kinetics may contribute, at least in part, to the development of DHF in larger mammals, including humans.
心肌肥厚与舒张性心力衰竭（DHF）相关，后者是一种收缩功能正常但心脏充盈动力学受损的综合征。DHF 的分子机制以及改变的交联循环的潜在作用尚未完全了解。因此，通过手术在大约 400 克雌性 Dunkin Hartley 豚鼠的胸升主动脉（AOB）上绑扎来诱导慢性压力超负荷（AOB）；作为对照，对年龄匹配的假手术动物进行手术。选择豚鼠以避免在其他小型啮齿动物模型中看到的肌球蛋白重链（MHC）同工型表达改变的混杂影响。通过超声心动图评估体内心功能；通过形态计量学分析确认心肌肥厚。AOB 导致左心室（LV）肥厚和舒张功能受损，收缩功能正常。生化分析显示， sham 对照和 AOB LV 中均仅表达β-MHC 同工型。在去皮的多细胞制剂、去皮的单个肌细胞片段和从冷冻（液氮）LV 制备的单个肌原纤维中评估肌丝功能。在 AOB 中，力依赖性 ATP 消耗（张力成本）和力重新发展（Ktr）的速率以及肌原纤维弛豫时间（Timelin）显著降低，表明交联循环动力学降低。AOB 肌细胞中最大 Ca2+激活力的发展显著降低，而肌丝 Ca2+敏感性没有变化。我们的结果表明，在β-MHC 小型动物 DHF 模型中交联循环变钝。交联循环动力学的降低可能至少部分导致包括人类在内的大型哺乳动物 DHF 的发展。
