RATIONALE Hypertrophied hearts switch from mainly using fatty acids (FAs) to an increased reliance on glucose for energy production. It has been shown that preserving FA oxidation (FAO) prevents the pathological shift of substrate preference, preserves cardiac function and energetics, and reduces cardiomyocyte hypertrophy during cardiac stresses. However, it remains elusive whether substrate metabolism regulates cardiomyocyte hypertrophy directly or via a secondary effect of improving cardiac energetics. OBJECTIVE The goal of this study was to determine the mechanisms of how preservation of FAO prevents the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS We cultured adult rat cardiomyocytes in a medium containing glucose and mixed-chain FAs and induced pathological hypertrophy by phenylephrine. Phenylephrine-induced hypertrophy was associated with increased glucose consumption and higher intracellular aspartate levels, resulting in increased synthesis of nucleotides, RNA, and proteins. These changes could be prevented by increasing FAO via deletion of ACC2 (acetyl-CoA-carboxylase 2) in phenylephrine-stimulated cardiomyocytes and in pressure overload-induced cardiac hypertrophy in vivo. Furthermore, aspartate supplementation was sufficient to reverse the antihypertrophic effect of ACC2 deletion demonstrating a causal role of elevated aspartate level in cardiomyocyte hypertrophy. 15N and 13C stable isotope tracing revealed that glucose but not glutamine contributed to increased biosynthesis of aspartate, which supplied nitrogen for nucleotide synthesis during cardiomyocyte hypertrophy. CONCLUSIONS Our data show that increased glucose consumption is required to support aspartate synthesis that drives the increase of biomass during cardiac hypertrophy. Preservation of FAO prevents the shift of metabolic flux into the anabolic pathway and maintains catabolic metabolism for energy production, thus preventing cardiac hypertrophy and improving myocardial energetics.

中文翻译：

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代谢重塑通过将葡萄糖引导至天冬氨酸生物合成来促进心脏肥大。

基本原理 肥厚的心脏从主要使用脂肪酸 (FAs) 转变为越来越依赖葡萄糖来产生能量。已经表明，保持 FA 氧化 (FAO) 可以防止底物偏好的病理变化，保持心脏功能和能量，并减少心脏应激期间的心肌细胞肥大。然而，底物代谢是直接调节心肌细胞肥大还是通过改善心脏能量的次级效应仍不清楚。目的 本研究的目的是确定 FAO 的保存如何防止心肌细胞肥大生长的机制。方法和结果 我们在含有葡萄糖和混合链 FA 的培养基中培养成年大鼠心肌细胞，并通过去氧肾上腺素诱导病理性肥大。去氧肾上腺素诱导的肥大与葡萄糖消耗增加和细胞内天冬氨酸水平升高有关，从而导致核苷酸、RNA 和蛋白质的合成增加。这些变化可以通过在去氧肾上腺素刺激的心肌细胞和压力超负荷诱导的体内心脏肥大中删除 ACC2（乙酰辅酶 A 羧化酶 2）来增加 FAO 来预防。此外，补充天冬氨酸足以逆转 ACC2 缺失的抗肥大作用，证明天冬氨酸水平升高在心肌细胞肥大中具有因果作用。15N 和 13C 稳定同位素示踪表明，葡萄糖而非谷氨酰胺有助于增加天冬氨酸的生物合成，天冬氨酸为心肌细胞肥大期间的核苷酸合成提供氮。结论 我们的数据表明，需要增加葡萄糖消耗来支持天冬氨酸合成，从而在心脏肥大期间驱动生物量的增加。FAO 的保存可防止代谢通量转移到合成代谢途径并维持分解代谢以产生能量，从而防止心脏肥大并改善心肌能量。