Aim: Adipose tissue (AT) dysfunction that occurs in both obesity and lipodystrophy is associated with the development of cardiomyopathy. However, it is unclear how dysfunctional AT induces cardiomyopathy due to limited animal models available. We have identified vacuolar H⁺-ATPase subunit V_od1, encoded by Atp6v0d1, as a master regulator of adipogenesis, and adipose-specific deletion of Atp6v0d1 (Atp6v0d1^AKO) in mice caused generalized lipodystrophy and spontaneous cardiomyopathy. Using this unique animal model, we explore the mechanism(s) underlying lipodystrophy-related cardiomyopathy./nMethods and Results: Atp6v0d1^AKO mice developed cardiac hypertrophy at 12 weeks, and progressed to heart failure at 28 weeks. The Atp6v0d1^AKO mouse hearts exhibited excessive lipid accumulation and altered lipid and glucose metabolism, which are typical for obesity- and diabetes-related cardiomyopathy. The Atp6v0d1^AKO mice developed cardiac insulin resistance evidenced by decreased IRS-1/2 expression in hearts. Meanwhile, the expression of forkhead box O1 (FoxO1), a transcription factor which plays critical roles in regulating cardiac lipid and glucose metabolism, was increased. RNA-seq data and molecular biological assays demonstrated reduced expression of myocardin, a transcription coactivator, in Atp6v0d1^AKO mouse hearts. RNA interference (RNAi), luciferase reporter and ChIP-qPCR assays revealed the critical role of myocardin in regulating IRS-1 transcription through the CArG-like element in IRS-1 promoter. Reducing IRS-1 expression with RNAi increased FoxO1 expression, while increasing IRS-1 expression reversed myocardin downregulation-induced FoxO1 upregulation in cardiomyocytes. In vivo, restoring myocardin expression specifically in Atp6v0d1^AKO cardiomyocytes increased IRS-1, but decreased FoxO1 expression. As a result, the abnormal expressions of metabolic genes in Atp6v0d1^AKO hearts were reversed, and cardiac dysfunctions were ameliorated. Myocardin expression was also reduced in high fat diet-induced diabetic cardiomyopathy and palmitic acid-treated cardiomyocytes. Moreover, increasing systemic insulin resistance with rosiglitazone restored cardiac myocardin expression and improved cardiac functions in Atp6v0d1^AKO mice./nConclusion: Atp6v0d1^AKO mice are a novel animal model for studying lipodystrophy- or metabolic dysfunction-related cardiomyopathy. Moreover, myocardin serves as a key regulator of cardiac insulin sensitivity and metabolic homeostasis, highlighting myocardin as a potential therapeutic target for treating lipodystrophy- and diabetes-related cardiomyopathy./n

中文翻译：

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在由空泡 H+-ATPase V0d1 亚基脂肪缺乏引起的脂肪营养不良小鼠模型中，Myocardin 通过增加 IRS-1 表达来逆转胰岛素抵抗并改善心肌病

目的：肥胖和脂肪营养不良中发生的脂肪组织（AT）功能障碍与心肌病的发生有关。然而，由于可用的动物模型有限，尚不清楚功能失调的 AT 如何诱发心肌病。我们已经鉴定出Atp6v0d1编码的液泡 H ⁺ -ATPase 亚基 V _{o d1 是脂肪生成的主要调节因子，并且小鼠中}Atp6v0d1 ( Atp6v0d1 ^AKO )的脂肪特异性缺失导致全身性脂肪营养不良和自发性心肌病。使用这种独特的动物模型，我们探索了脂肪营养不良相关心肌病的潜在机制。/n 方法和结果：Atp6v0d1 ^AKO小鼠在 12 周时出现心脏肥大，并在 28 周时进展为心力衰竭。 Atp6v0d1 AKO^小鼠心脏表现出过度的脂质积累以及脂质和葡萄糖代谢的改变，这是肥胖和糖尿病相关心肌病的典型特征。 Atp6v0d1 ^{AKO小鼠出现了心脏胰岛素抵抗}，心脏中 IRS-1/2 表达降低证明了这一点。同时，叉头盒O1（FoxO1）的表达增加，叉头盒O1是一种在调节心脏脂质和葡萄糖代谢中起关键作用的转录因子。 RNA-seq 数据和分子生物学测定表明Atp6v0d1 ^AKO小鼠心脏中心肌素（一种转录共激活因子）的表达降低。 RNA 干扰 (RNAi)、荧光素酶报告基因和 ChIP-qPCR 检测揭示了心肌素通过 IRS-1 启动子中的 CArG 样元件在调节 IRS-1 转录中的关键作用。用 RNAi 减少 IRS-1 表达会增加 FoxO1 表达，而增加 IRS-1 表达会逆转心肌细胞中心肌素下调诱导的 FoxO1 上调。在体内，恢复Atp6v0d1 ^AKO心肌细胞中的心肌素表达会增加IRS-1的表达，但会降低FoxO1的表达。结果，Atp6v0d1 ^AKO心脏中代谢基因的异常表达被逆转，心脏功能障碍得到改善。在高脂肪饮食诱发的糖尿病心肌病和棕榈酸处理的心肌细胞中，心肌蛋白的表达也有所降低。此外，用罗格列酮增加全身胰岛素抵抗可恢复Atp6v0d1 ^AKO小鼠的心肌蛋白表达并改善心脏功能。/n 结论：Atp6v0d1 ^AKO 小鼠是研究脂肪营养不良或代谢功能障碍相关心肌病的新型动物模型。此外，心肌素是心脏胰岛素敏感性和代谢稳态的关键调节剂，凸显心肌素作为治疗脂肪营养不良和糖尿病相关心肌病的潜在治疗靶点。/n