The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP). Conversely, exercise enhanced HDAC4-NT levels, and mice with a cardiomyocyte-specific deletion of Hdac4 show reduced exercise capacity, which was characterized by cardiac fatigue and increased expression of Nr4a1. Mechanistically, we found that NR4A1 negatively regulated contractile function in a manner that depended on the HBP and the calcium sensor STIM1. Our work describes a new regulatory axis in which epigenetic regulation of a metabolic pathway affects calcium handling. Activation of this axis during intermittent physiological stress promotes cardiac function, whereas its impairment in sustained pathological cardiac stress leads to heart failure.

中文翻译：

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组蛋白脱乙酰基酶4的蛋白水解片段通过调节己糖胺的生物合成途径来保护心脏免于衰竭。

应激反应的表观遗传阻遏物组蛋白脱乙酰基酶4（HDAC4）调节心脏基因的表达。在这里，我们表明，在衰竭的小鼠心脏中，HDAC4的N端蛋白水解衍生的HDAC4片段的水平低于健康对照组的心脏。病毒介导的编码HDAC4-NT的Hdac4基因部分转移到小鼠心肌中，可保护心脏免于重塑和衰竭。这与编码核孤儿受体的Nr4a1的表达降低以及己糖胺生物合成途径（HBP）的NR4A1依赖性激活降低有关。相反，运动增强了HDAC4-NT的水平，具有心肌细胞特异性Hdac4缺失的小鼠表现出降低的运动能力，其特征是心脏疲劳和Nr4a1表达增加。机械上，我们发现NR4A1依赖于HBP和钙传感器STIM1负调节收缩功能。我们的工作描述了新的调控轴，其中代谢途径的表观遗传调控影响钙的处理。在间歇性生理压力期间激活此轴可增强心脏功能，而其在持续病理性心脏压力中的损伤会导致心力衰竭。