Currently there is an unmet need for treatments that can prevent hypertrophic cardiomyopathy (HCM). Using a murine model we previously identified that HCM causing cardiac troponin I mutation Gly203Ser (cTnI-G203S) is associated with increased mitochondrial metabolic activity, consistent with the human condition. These alterations precede development of the cardiomyopathy. Here we examine the efficacy of in vivo treatment of cTnI-G203S mice with a peptide derived against the α-interaction domain of the cardiac L-type calcium channel (AID-TAT) on restoring mitochondrial metabolic activity, and preventing HCM. cTnI-G203S or age-matched wt mice were treated with active or inactive AID-TAT. Following treatment, targeted metabolomics was utilized to evaluate myocardial substrate metabolism. Cardiac myocyte mitochondrial metabolic activity was assessed as alterations in mitochondrial membrane potential and flavoprotein oxidation. Cardiac morphology and function were examined using echocardiography. Cardiac uptake was assessed using an in vivo multispectral imaging system. We identified alterations in six biochemical intermediates in cTnI-G203S hearts consistent with increased anaplerosis. We also reveal that AID-TAT treatment of precardiomyopathic cTnI-G203S mice, but not mice with established cardiomyopathy, restored cardiac myocyte mitochondrial membrane potential and flavoprotein oxidation, and prevented myocardial hypertrophy. Importantly, AID-TAT was rapidly targeted to the heart, and not retained by the liver or kidneys. Overall, we identify biomarkers of HCM resulting from the cTnI mutation Gly203Ser, and present a safe, preventative therapy for associated cardiomyopathy. Utilizing AID-TAT to modulate cardiac metabolic activity may be beneficial in preventing HCM in “at risk” patients with identified Gly203Ser gene mutations.

当前，对于可以预防肥厚性心肌病（HCM）的治疗的需求尚未得到满足。使用鼠模型，我们先前确定了导致心肌肌钙蛋白I突变Gly203Ser（cTnI-G203S）的HCM与线粒体代谢活性的增加有关，这与人类的状况相符。这些改变先于心肌病的发展。在这里，我们研究了用抗心脏L型钙通道（AID-TAT）的α相互作用域衍生的肽体内治疗cTnI-G203S小鼠恢复线粒体代谢活性和预防HCM的功效。cTnI的-G203S或年龄匹配的重量用活性或非活性AID-TAT治疗小鼠。治疗后，利用靶向代谢组学评估心肌底物代谢。心肌细胞线粒体的代谢活性被评估为线粒体膜电位和黄素蛋白氧化的改变。使用超声心动图检查心脏形态和功能。使用体内多光谱成像系统评估心脏摄取。我们在cTnI-G203S心脏中发现了六个生化中间体的改变，与动脉粥样硬化的增加一致。我们还揭示了AID-TAT治疗心肌病前cTnI-G203S小鼠，但没有建立起心肌病的小鼠，恢复了心肌细胞线粒体膜电位和黄素蛋白氧化，并预防了心肌肥大。重要的是，AID-TAT迅速靶向心脏，并没有被肝脏或肾脏保留。总体而言，我们确定了cTnI突变Gly203Ser导致的HCM生物标志物，并提出了一种安全，预防性的相关心肌病治疗方法。利用AID-TAT调节心脏代谢活性可能对预防具有确定的Gly203Ser基因突变的“高危”患者的HCM有益。