Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of alpha motor neurons and skeletal muscle atrophy. The disease is caused by mutations of the SMN1 gene that result in reduced functional expression of survival motor neuron (SMN) protein. SMN is ubiquitously expressed, and there have been reports of cardiovascular dysfunction in the most severe SMA patients and animal models of the disease. In this study, we directly assessed the function of cardiomyocytes isolated from a severe SMA model mouse and cardiomyocytes generated from patient-derived IPSCs. Consistent with impaired cardiovascular function at the very early disease stages in mice, heart failure markers such as brain natriuretic peptide were significantly elevated. Functionally, cardiomyocyte relaxation kinetics were markedly slowed and the T50 for Ca2+ sequestration increased to 146 ± 4 ms in SMN-deficient cardiomyocytes from 126 ± 4 ms in wild type cells. Reducing SMN levels in cardiomyocytes from control patient IPSCs slowed calcium reuptake similar to SMA patent-derived cardiac cells. Importantly, restoring SMN increased calcium reuptake rate. Taken together, these results indicate that SMN deficiency impairs cardiomyocyte function at least partially through intracellular Ca2+ cycling dysregulation.

中文翻译：

---

SMN 缺乏会破坏 SMA 小鼠和患者来源的 iPSC 心肌细胞中的 SERCA2 表达和细胞内 Ca2+ 信号传导。

脊髓性肌萎缩症 (SMA) 是一种以 α 运动神经元丧失和骨骼肌萎缩为特征的神经退行性疾病。该疾病是由 SMN1 基因突变引起的，该突变导致运动神经元存活 (SMN) 蛋白的功能表达降低。SMN 普遍表达，并且在最严重的 SMA 患者和该疾病的动物模型中有心血管功能障碍的报道。在这项研究中，我们直接评估了从严重 SMA 模型小鼠中分离的心肌细胞和从患者来源的 IPSC 中产生的心肌细胞的功能。与小鼠早期疾病阶段心血管功能受损一致，脑利钠肽等心力衰竭标志物显着升高。在功能上，心肌细胞松弛动力学明显减慢，并且 SMN 缺陷型心肌细胞中 Ca2+ 螯合的 T50 从野生型细胞中的 126 ± 4 ms 增加到 146 ± 4 ms。降低对照患者 IPSC 的心肌细胞中的 SMN 水平会减缓钙的再摄取，类似于 SMA 专利衍生的心肌细胞。重要的是，恢复 SMN 会增加钙的再摄取率。总之，这些结果表明 SMN 缺乏至少部分通过细胞内 Ca2+ 循环失调损害心肌细胞功能。