PTRF/Cavin-1 Deficiency Causes Cardiac Dysfunction Accompanied by Cardiomyocyte Hypertrophy and Cardiac Fibrosis

Mutations in the PTRF/Cavin-1 gene cause congenital generalized lipodystrophy type 4 (CGL4) associated with myopathy. Additionally, long-QT syndrome and fatal cardiac arrhythmia are observed in patients with CGL4 who have homozygous PTRF/Cavin-1 mutations. PTRF/Cavin-1 deficiency shows reductions of caveolae and caveolin-3 (Cav3) protein expression in skeletal muscle, and Cav3 deficiency in the heart causes cardiac hypertrophy with loss of caveolae. However, it remains unknown how loss of PTRF/Cavin-1 affects cardiac morphology and function. Here, we present a characterization of the hearts of PTRF/Cavin-1-null (PTRF−/−) mice. Electron microscopy revealed the reduction of caveolae in cardiomyocytes of PTRF−/− mice. PTRF−/− mice at 16 weeks of age developed a progressive cardiomyopathic phenotype with wall thickening of left ventricles and reduced fractional shortening evaluated by echocardiography. Electrocardiography revealed that PTRF−/− mice at 24 weeks of age had low voltages and wide QRS complexes in limb leads. Histological analysis showed cardiomyocyte hypertrophy accompanied by progressive interstitial/perivascular fibrosis. Hypertrophy-related fetal gene expression was also induced in PTRF−/− hearts. Western blotting analysis and quantitative RT-PCR revealed that Cav3 expression was suppressed in PTRF−/− hearts compared with that in wild-type (WT) ones. ERK1/2 was activated in PTRF−/− hearts compared with that in WT ones. These results suggest that loss of PTRF/Cavin-1 protein expression is sufficient to induce a molecular program leading to cardiomyocyte hypertrophy and cardiomyopathy, which is partly attributable to Cav3 reduction in the heart.PTRF/Cavin-1基因的突变可引发伴肌病的4型先天性全身性脂肪营养不良（congenital generalized lipodystrophy type 4, CGL4）。此外，携带纯合PTRF/Cavin-1突变的CGL4患者还会出现长QT综合征与致命性心脏心律失常。PTRF/Cavin-1缺失会导致骨骼肌内的窖小体（caveolae）与窖蛋白3（caveolin-3, Cav3）的蛋白表达水平下降；而心脏内的Cav3缺失则会引发伴随窖小体丢失的心肌肥厚。不过目前学界尚不清楚PTRF/Cavin-1的缺失如何影响心脏的形态与功能。本研究对PTRF/Cavin-1敲除（PTRF−/−）小鼠的心脏开展了表征分析。电子显微镜观察显示，PTRF−/−小鼠的心肌细胞内窖小体数量减少。16周龄的PTRF−/−小鼠出现进行性心肌病表型，表现为左心室壁增厚，经超声心动图检测的短轴缩短率降低。心电图检查结果显示，24周龄的PTRF−/−小鼠肢体导联呈现低电压与宽QRS波群。组织学分析表明，心肌细胞肥厚伴随进行性间质/血管周纤维化。PTRF−/−小鼠心脏中还诱导出了肥厚相关的胎儿基因表达。蛋白质印迹（Western blotting）分析与定量逆转录聚合酶链反应（quantitative RT-PCR）结果显示，与野生型（wild-type, WT）小鼠相比，PTRF−/−小鼠心脏中的Cav3表达受到抑制。相较于野生型小鼠，PTRF−/−小鼠心脏中的ERK1/2被激活。上述结果表明，PTRF/Cavin-1蛋白表达的缺失足以诱导引发心肌细胞肥厚与心肌病的分子程序，这一效应在一定程度上可归因于心脏内Cav3水平的降低。