Sikder Kunal, Phillips Elizabeth, Zhong Zhijiu, Wang Nadan, Saunders Jasmine, Mothy David, Kossenkov Andrew, Schneider Timothy, Nichtova Zuzana, Csordas Gyorgy, Margulies Kenneth B, Choi Jason C
bioRxiv. 2023 Jun 7:2023.02.14.528563. doi: 10.1101/2023.02.14.528563.
Mutations in the gene encoding nuclear lamins A/C cause a diverse array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the molecular perturbations emanating from mutations, an integrative understanding of the pathogenesis leading to cardiac dysfunction remains elusive. Using a novel cell-type specific deletion mouse model capable of translatome profiling, we found that cardiomyocyte-specific deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Prior to the onset of cardiac dysfunction, lamin A/C-depleted cardiomyocytes displayed nuclear envelope deterioration, golgi dilation/fragmentation, and CREB3-mediated golgi stress activation. Translatome profiling identified upregulation of Med25, a transcriptional co-factor that can selectively dampen UPR axes. Autophagy is disrupted in the hearts of these mice, which can be recapitulated by disrupting the golgi or inducing nuclear damage by increased matrix stiffness. Systemic administration of pharmacological modulators of autophagy or ER stress significantly improved the cardiac function. These studies support a hypothesis wherein stress responses emanating from the perinuclear space contribute to the development of cardiomyopathy.
Interplay of stress responses underlying the development of cardiomyopathy.
编码核纤层蛋白A/C的基因突变会引发一系列组织选择性疾病，其中心脏是最常受影响的器官。尽管在理解由这些突变引发的分子扰动方面取得了进展，但对导致心脏功能障碍的发病机制的综合理解仍然难以捉摸。使用一种能够进行翻译组分析的新型细胞类型特异性基因敲除小鼠模型，我们发现成年小鼠心肌细胞特异性基因敲除会导致快速心肌病伴病理重塑。在心脏功能障碍发作之前，缺乏核纤层蛋白A/C的心肌细胞表现出核膜退化、高尔基体扩张/碎片化以及CREB3介导的高尔基体应激激活。翻译组分析确定了Med25的上调，Med25是一种转录辅因子，可选择性抑制未折叠蛋白反应（UPR）轴。这些小鼠心脏中的自噬被破坏，这可以通过破坏高尔基体或通过增加基质硬度诱导核损伤来重现。全身给予自噬或内质网应激的药理调节剂可显著改善心脏功能。这些研究支持了一种假说，即核周空间产生的应激反应促成了心肌病的发展。
心肌病发展过程中应激反应的相互作用。
