Dysferlin deficiency blunts β-adrenergic-dependent lusitropic function of mouse heart.
Dysferlin deficiency blunts β-adrenergic-dependent lusitropic function of mouse heart.
复制标题
Dysferlin 缺乏会削弱小鼠心脏的β-肾上腺素依赖的松弛功能。
DOI：
10.1113/jp271225
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Jin,J-P
中科院分区：
文献类型：
--
作者：
Wei,Bin;Wei,Hongguang;Jin,J-P
关键点dysferlin缺乏导致肢带型肌营养不良症2B和Miyoshi肌病伴心脏受累，导致扩张型心肌病和心力衰竭。dysferlin心肌病的发病机制和病理生理学尚未完全了解。我们研究了年轻dysferlin基因敲除小鼠的心脏表型，以研究其主要病理和病理生理学变化。与野生型对照相比，dysferlin缺陷型心肌细胞显示出较慢的Ca 2+再螯合，Dysferlin缺乏减弱了β-肾上腺素能对舒张和泵血功能的影响，Dysferlin缺乏增加了磷酸化水平，Dysferlin是一种细胞膜结合蛋白，在骨骼肌和心肌细胞的修复过程中起重要作用。dysferlin缺乏导致肢带型肌营养不良症2B（LGMD 2B）和Miyoshi肌病。在心肌中，dysferlin位于闰盘和横小管膜上。dysferlin的缺失导致心肌细胞死亡，特别是在衰老的心脏中，导致LGM 2B患者的扩张型心肌病和心力衰竭。为了了解dysferlin心肌病的主要发病机制和病理生理学，我们研究了年轻成年dysferlin基因敲除小鼠的心脏表型，发现早期心肌肥大，基线心功能得到很大补偿。从dysferlin缺陷小鼠中分离的心肌细胞在没有外部负荷的情况下显示出正常的缩短和再延长速度，具有正常的收缩期Ca 2+峰值，但比野生型对照更慢的Ca 2+再螯合。与野生型心脏相比，异丙肾上腺素对dysferlin缺陷小鼠心脏的舒张速度、左心室收缩压和每搏输出量的影响减弱。年轻dysferlin缺陷小鼠心脏表达肌丝蛋白的正常亚型，而心室肌球蛋白轻链2的磷酸化显著增加，这意味着对受损的lusitropic功能的分子反应。舒张期心功能不全的这些早期表型和心肌对β-肾上腺素能刺激的钝性舒张反应表明dysferlin心肌病的一种新的致病机制。
Key pointsDeficiency of dysferlin causes limb‐girdle muscular dystrophy 2B and Miyoshi myopathy with cardiac involvement that leads to dilated cardiomyopathy and heart failure. The pathogenesis and pathophysiology of dysferlin cardiomyopathy are not fully understood.We studied cardiac phenotypes of young dysferlin gene knockout mice to investigate the primary pathological and pathophysiological changes.In comparison with wild‐type controls, dysferlin‐deficient cardiomyocytes showed slower Ca2+re‐sequestration, and dysferlin deficiency blunted the β‐adrenergic effect on relaxation and pumping function ofex vivoworking hearts.Dysferlin deficiency increased phosphorylation of ventricular myosin light chain 2, suggesting a compensatory response to the impaired cardiac lusitropic function.The data suggest that delayed calcium re‐sequestration and post‐translational modification of myofilament proteins may provide potential targets to develop new treatments for dysferlin cardiomyopathy.AbstractDysferlin is a cell membrane bound protein with a role in the repair of skeletal and cardiac muscle cells. Deficiency of dysferlin leads to limb‐girdle muscular dystrophy 2B (LGMD2B) and Miyoshi myopathy. In cardiac muscle, dysferlin is located at the intercalated disc and transverse tubule membranes. Loss of dysferlin causes death of cardiomyocytes, notably in ageing hearts, leading to dilated cardiomyopathy and heart failure in LGM2B patients. To understand the primary pathogenesis and pathophysiology of dysferlin cardiomyopathy, we studied cardiac phenotypes of young adult dysferlin knockout mice and found early myocardial hypertrophy with largely compensated baseline cardiac function. Cardiomyocytes isolated from dysferlin‐deficient mice showed normal shortening and re‐lengthening velocities in the absence of external load with normal peak systolic Ca2+but slower Ca2+re‐sequestration than wild‐type controls. The effects of isoproterenol on relaxation velocity, left ventricular systolic pressure and stroke volume were blunted in dysferlin‐deficient mouse hearts compared with that in wild‐type hearts. Young dysferlin‐deficient mouse hearts expressed normal isoforms of myofilament proteins whereas the phosphorylation of ventricular myosin light chain 2 was significantly increased, implying a molecular response to the impaired lusitropic function. These early phenotypes of diastolic cardiac dysfunction and blunted lusitropic response of cardiac muscle to β‐adrenergic stimulation indicate a novel pathogenic mechanism of dysferlin cardiomyopathy.