Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona; Department of Biomedical Engineering, University of Arizona, Tucson, Arizona;
Department of Physiology, University of Arizona, Tucson, Arizona; Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona;
Am J Physiol Heart Circ Physiol. 2016 Jul 1;311(1):H125-36. doi: 10.1152/ajpheart.00592.2015. Epub 2016 May 6.
Familial hypertrophic cardiomyopathy (HCM) is a disease of the sarcomere and may lead to hypertrophic, dilated, restrictive, and/or arrhythmogenic cardiomyopathy, congestive heart failure, or sudden cardiac death. We hypothesized that hearts from transgenic HCM mice harboring a mutant myosin heavy chain increase the energetic cost of contraction in a sex-specific manner. To do this, we assessed Ca(2+) sensitivity of tension and crossbridge kinetics in demembranated cardiac trabeculas from male and female wild-type (WT) and HCM hearts at an early time point (2 mo of age). We found a significant effect of sex on Ca(2+) sensitivity such that male, but not female, HCM mice displayed a decrease in Ca(2+) sensitivity compared with WT counterparts. The HCM transgene and sex significantly impacted the rate of force redevelopment by a rapid release-restretch protocol and tension cost by the ATPase-tension relationship. In each of these measures, HCM male trabeculas displayed a gain-of-function when compared with WT counterparts. In addition, cardiac remodeling measured by echocardiography, histology, morphometry, and posttranslational modifications demonstrated sex- and HCM-specific effects. In conclusion, female and male HCM mice display sex dimorphic crossbridge kinetics accompanied by sex- and HCM-dependent cardiac remodeling at the morphometric, histological, and cellular level.
家族性肥厚型心肌病 (HCM) 是一种肌节疾病，可能导致肥厚型、扩张型、限制型和/或心律失常性心肌病、充血性心力衰竭或心源性猝死。我们假设携带突变肌球蛋白重链的转基因 HCM 小鼠的心脏会以性别特异性的方式增加收缩的能量成本。为此，我们在 2 个月龄的早期时间点评估了雄性和雌性野生型 (WT) 和 HCM 心脏去膜心肌横管中张力和交联动力学的 Ca(2+) 敏感性。我们发现性别对 Ca(2+) 敏感性有显著影响，即雄性但不是雌性 HCM 小鼠与 WT 对应物相比，Ca(2+) 敏感性降低。HCM 转基因和性别显著影响了快速释放-拉伸方案的力再发展率和 ATPase-张力关系的张力成本。在这些措施中，与 WT 对应物相比，HCM 雄性横管显示出功能获得。此外，通过超声心动图、组织学、形态计量学和翻译后修饰测量的心脏重构表现出性别和 HCM 特异性的影响。总之，雌性和雄性 HCM 小鼠表现出性别二态性交联动力学，并伴有形态计量学、组织学和细胞水平上的性别和 HCM 依赖性心脏重构。
