Aims Aging impairs cardiac function and increases susceptibility to myocardial ischemic injury. Cardiac myosin light chain kinase (MLCK3) phosphorylates cardiac myosin regulatory light chain (MLC2), controlling sarcomere organization and cardiomyocyte contraction. Dysregulation of MLCK3 and phosphorylated MLC2 (p-MLC2) contributes to heart failure after myocardial infarction (MI). We aimed at exploring how the MLCK3-p-MLC2 axis changes in aging hearts post MI and at investigating the underlying regulatory mechanisms. Methods and results We generated adult (3 months) and aged (30 months) MI mouse models to compare their cardiac performance, and then detected MLCK3 expression and MLC2 activity. Aging increased the size of MI-induced infarctions and promoted cardiac contractile dysfunction. Furthermore, MLCK3 expression and MLC2 activity increased in adult hearts after MI, but not in aged hearts. miR-146a was found consistently increased in adult and aged hearts post-MI. Mechanistic analyses performed in vitro demonstrated that miR-146a-5p downregulated matrix metalloprotease (MMP)2/16 expression in cardiomyocytes. This downregulation in turn increased MLCK3 expression and MLC2 activity. However, miR-146a-5p failed to regulate the MMP2/16-MLCK3-p-MLC2 axis in senescent cardiomyocytes or in cardiac miR-146a conditional knockout mice, with the latter experiencing an exacerbated deterioration of cardiac function post-MI. Conclusion These results suggest that increase of MLCK3 and p-MLC2 contents through decreasing MMP2/16 by miR-146a-5p represents a compensatory mechanism that can protect cardiac contractile function after MI. Aging impairs this miR-146a-5p-regulated MMP2/16-MLCK3-p-MLC2 contractile axis, leading to compromised contractile function and increased susceptibility to heart failure.

中文翻译：

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miR-146a-5p 对 MMP2/16-MLCK3 的调节受损增加了衰老小鼠对心肌缺血损伤的易感性

目的 衰老会损害心脏功能并增加对心肌缺血损伤的易感性。心肌肌球蛋白轻链激酶 (MLCK3) 磷酸化心肌肌球蛋白调节轻链 (MLC2)，从而控制肌节组织和心肌细胞收缩。MLCK3 和磷酸化 MLC2 (p-MLC2) 的失调导致心肌梗死 (MI) 后的心力衰竭。我们的目的是探索 MLCK3-p-MLC2 轴如何在 MI 后老化心脏中发生变化，并研究潜在的调节机制。方法和结果 我们生成了成人（3 个月）和老年（30 个月）MI 小鼠模型来比较它们的心脏性能，然后检测 MLCK3 表达和 MLC2 活性。衰老增加了 MI 诱发的梗死面积并促进了心脏收缩功能障碍。此外，MLCK3 表达和 MLC2 活性在 MI 后成人心脏中增加，但在老年心脏中没有。发现 miR-146a 在 MI 后成人和老年心脏中持续增加。体外进行的机制分析表明，miR-146a-5p 下调了心肌细胞中基质金属蛋白酶 (MMP)2/16 的表达。这种下调反过来增加了 MLCK3 表达和 MLC2 活性。然而，miR-146a-5p 未能在衰老的心肌细胞或心脏 miR-146a 条件性敲除小鼠中调节 MMP2/16-MLCK3-p-MLC2 轴，后者在 MI 后心功能恶化加剧。结论 这些结果表明，miR-146a-5p 通过降低 MMP2/16 来增加 MLCK3 和 p-MLC2 含量代表了一种可以保护 MI 后心脏收缩功能的代偿机制。