The human cardiovascular system has adapted to function optimally in Earth's 1G gravity, and microgravity conditions cause myocardial abnormalities, including atrophy and dysfunction. However, the underlying mechanisms linking microgravity and cardiac anomalies are incompletely understood. In this study, we investigated whether and how calpain activation promotes myocardial abnormalities under simulated microgravity conditions. Simulated microgravity was induced by tail suspension in mice with cardiomyocyte-specific deletion of Capns1, which disrupts activity and stability of calpain-1 and calpain-2, and their WT littermates. Tail suspension time-dependently reduced cardiomyocyte size, heart weight, and myocardial function in WT mice, and these changes were accompanied by calpain activation, NADPH oxidase activation, and oxidative stress in heart tissues. The effects of tail suspension were attenuated by deletion of Capns1. Notably, the protective effects of Capns1 deletion were associated with the prevention of phosphorylation of Ser-345 on p47phox and attenuation of ERK1/2 and p38 activation in hearts of tail-suspended mice. Using a rotary cell culture system, we simulated microgravity in cultured neonatal mouse cardiomyocytes and observed decreased total protein/DNA ratio and induced calpain activation, phosphorylation of Ser-345 on p47phox, and activation of ERK1/2 and p38, all of which were prevented by calpain inhibitor-III. Furthermore, inhibition of ERK1/2 or p38 attenuated phosphorylation of Ser-345 on p47phox in cardiomyocytes under simulated microgravity. This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities.

中文翻译：

---

钙蛋白酶激活通过 p38 和 ERK1/2 MAPK 途径介导小鼠微重力诱导的心肌异常

人类心血管系统已适应在地球 1G 重力下发挥最佳功能，而微重力条件会导致心肌异常，包括萎缩和功能障碍。然而，微重力和心脏异常之间的潜在机制尚不完全清楚。在这项研究中，我们研究了在模拟微重力条件下钙蛋白酶激活是否以及如何促进心肌异常。心肌细胞特异性缺失 Capns1 的小鼠通过尾部悬浮诱导模拟微重力，这会破坏 calpain-1 和 calpain-2 及其 WT 同窝小鼠的活性和稳定性。尾部悬浮时间依赖性地降低了WT小鼠的心肌细胞大小、心脏重量和心肌功能，并且这些变化伴随着钙蛋白酶激活、NADPH氧化酶激活、和心脏组织的氧化应激。Capns1 的缺失减弱了尾部悬浮的影响。值得注意的是，Capns1 缺失的保护作用与防止悬尾小鼠心脏中 p47phox 上 Ser-345 的磷酸化以及 ERK1/2 和 p38 激活的减弱有关。使用旋转细胞培养系统，我们在培养的新生小鼠心肌细胞中模拟微重力，观察到总蛋白/DNA比率下降，诱导钙蛋白酶激活、p47phox上的Ser-345磷酸化以及ERK1/2和p38激活，所有这些都被阻止通过钙蛋白酶抑制剂-III。此外，在模拟微重力下，抑制 ERK1/2 或 p38 可减弱心肌细胞 p47phox 上 Ser-345 的磷酸化。这项研究首次证明钙蛋白酶通过 ERK1/2 和 p38 途径促进 p47phox 磷酸化，从而促进微重力下 NADPH 氧化酶激活和心肌异常。因此，钙蛋白酶抑制可能是减少微重力引起的心肌异常的有效治疗方法。