PDF(Pubmed)
Abstract：
UNASSIGNED: PERM1 is a striated muscle-specific regulator of mitochondrial bioenergetics. We previously demonstrated that PERM1 is downregulated in the failing heart and that PERM1 positively regulates metabolic genes known as targets of the transcription factor ERRα and its coactivator PGC-1α in cultured cardiomyocytes. The aims of this study were to determine the effect of loss of PERM1 on cardiac function and energetics using newly generated Perm1-knockout (Perm1 -/-) mice and to investigate the molecular mechanisms of its transcriptional control.
UNASSIGNED: Echocardiography showed that ejection fraction and fractional shortening were lower in Perm1 -/- mice than in wild-type mice (both p < 0.05), and the phosphocreatine-to-ATP ratio was decreased in Perm1 -/- hearts (p < 0.05), indicating reduced contractile function and energy reserves of the heart. Integrated proteomic and metabolomic analyses revealed downregulation of oxidative phosphorylation and upregulation of glycolysis and polyol pathways in Perm1 -/- hearts. To examine whether PERM1 regulates energy metabolism through ERRα, we performed co-immunoprecipitation assays, which showed that PERM1 bound to ERRα in cardiomyocytes and the mouse heart. DNA binding and reporter gene assays showed that PERM1 was localized to and activated the ERR target promoters partially through ERRα. Mass spectrometry-based screening in cardiomyocytes identified BAG6 and KANK2 as potential PERM1\'s binding partners in transcriptional regulation. Mammalian one-hybrid assay, in which PERM1 was fused to Gal4 DNA binding domain, showed that the recruitment of PERM1 to a gene promoter was sufficient to activate transcription, which was blunted by silencing of either PGC-1α, BAG6, or KANK2.
UNASSIGNED: This study demonstrates that PERM1 is an essential regulator of cardiac energetics and function and that PERM1 is a novel transcriptional coactivator in the ERRα/PGC-1α axis that functionally interacts with BAG6 and KANK2.
UNASSIGNED: Echocardiography showed that ejection fraction and fractional shortening were lower in Perm1 -/- mice than in wild-type mice (both p < 0.05), and the phosphocreatine-to-ATP ratio was decreased in Perm1 -/- hearts (p < 0.05), indicating reduced contractile function and energy reserves of the heart. Integrated proteomic and metabolomic analyses revealed downregulation of oxidative phosphorylation and upregulation of glycolysis and polyol pathways in Perm1 -/- hearts. To examine whether PERM1 regulates energy metabolism through ERRα, we performed co-immunoprecipitation assays, which showed that PERM1 bound to ERRα in cardiomyocytes and the mouse heart. DNA binding and reporter gene assays showed that PERM1 was localized to and activated the ERR target promoters partially through ERRα. Mass spectrometry-based screening in cardiomyocytes identified BAG6 and KANK2 as potential PERM1\'s binding partners in transcriptional regulation. Mammalian one-hybrid assay, in which PERM1 was fused to Gal4 DNA binding domain, showed that the recruitment of PERM1 to a gene promoter was sufficient to activate transcription, which was blunted by silencing of either PGC-1α, BAG6, or KANK2.
UNASSIGNED: This study demonstrates that PERM1 is an essential regulator of cardiac energetics and function and that PERM1 is a novel transcriptional coactivator in the ERRα/PGC-1α axis that functionally interacts with BAG6 and KANK2.
摘要：
未经批准：PERM1是线粒体生物能学的横纹肌特异性调节因子。我们先前证明了PERM1在衰竭的心脏中下调，并且PERM1正调节被称为转录因子ERRα及其共激活剂PGC-1α在培养的心肌细胞中的靶标的代谢基因。这项研究的目的是使用新产生的Perm1敲除（Perm1-/-）小鼠确定PERM1丢失对心脏功能和能量学的影响，并研究其转录控制的分子机制。
UNASSIGNED：超声心动图显示，Perm1-/-小鼠的射血分数和缩短分数低于野生型小鼠（均p<0.05），Perm1-/-心脏的磷酸肌酸与ATP比率降低（p<0.05），表明心脏的收缩功能和能量储备降低。整合的蛋白质组学和代谢组学分析揭示了Perm1-/-心脏中氧化磷酸化的下调和糖酵解和多元醇途径的上调。为了检查PERM1是否通过ERRα调节能量代谢，我们进行了免疫共沉淀试验,结果表明，PERM1与心肌细胞和小鼠心脏中的ERRα结合。DNA结合和报告基因分析表明，PERM1定位并部分通过ERRα激活ERR靶启动子。在心肌细胞中基于质谱的筛选鉴定BAG6和KANK2为转录调控中潜在的PERM1结合配偶体。哺乳动物单杂交试验，其中PERM1与Gal4DNA结合域融合，表明PERM1募集到基因启动子足以激活转录，它被PGC-1α的沉默所钝化，BAG6或KANK2。
UNASSIGNED：这项研究表明PERM1是心脏能量学和功能的重要调节因子，并且PERM1是ERRα/PGC-1α轴中的新型转录共激活因子，可与BAG6和KANK2功能性相互作用。
UNASSIGNED：超声心动图显示，Perm1-/-小鼠的射血分数和缩短分数低于野生型小鼠（均p<0.05），Perm1-/-心脏的磷酸肌酸与ATP比率降低（p<0.05），表明心脏的收缩功能和能量储备降低。整合的蛋白质组学和代谢组学分析揭示了Perm1-/-心脏中氧化磷酸化的下调和糖酵解和多元醇途径的上调。为了检查PERM1是否通过ERRα调节能量代谢，我们进行了免疫共沉淀试验,结果表明，PERM1与心肌细胞和小鼠心脏中的ERRα结合。DNA结合和报告基因分析表明，PERM1定位并部分通过ERRα激活ERR靶启动子。在心肌细胞中基于质谱的筛选鉴定BAG6和KANK2为转录调控中潜在的PERM1结合配偶体。哺乳动物单杂交试验，其中PERM1与Gal4DNA结合域融合，表明PERM1募集到基因启动子足以激活转录，它被PGC-1α的沉默所钝化，BAG6或KANK2。
UNASSIGNED：这项研究表明PERM1是心脏能量学和功能的重要调节因子，并且PERM1是ERRα/PGC-1α轴中的新型转录共激活因子，可与BAG6和KANK2功能性相互作用。
