Long-chain fatty acid oxidation is frequently impaired in primary and systemic metabolic diseases affecting the heart, thus therapeutically increasing reliance on normally minor energetic substrates, such as ketones and medium chain fatty acids, could benefit cardiac health. However, the molecular fundamentals of this therapy are not fully known. Here, we explored the ability of octanoate, an eight-carbon medium-chain fatty acid known as an unregulated mitochondrial energetic substrate, to ameliorate cardiac hypertrophy in long-chain fatty acid oxidation deficient hearts due to carnitine palmitoyltransferase 2 deletion (Cpt2^M-/-). CPT2 converts acylcarnitines to acyl-CoAs in the mitochondrial matrix for oxidative bioenergetic metabolism. In Cpt2^M-/- mice, high octanoate-ketogenic diet failed to alleviate myocardial hypertrophy, dysfunction, and acylcarnitine accumulation suggesting that this alternative substrate is not sufficiently compensatory for energy provision. Aligning this outcome, we identified a major metabolic distinction between muscles and liver, wherein heart and skeletal muscle mitochondria were unable to oxidize free octanoate but liver was able to oxidize free octanoate. Liver mitochondria, but not heart or muscle, highly expressed medium-chain acyl-CoA synthetases, potentially enabling octanoate activation for oxidation and circumventing acylcarnitine-shuttling. Conversely, octanoylcarnitine was oxidized by liver, skeletal muscle, and heart, with rates in heart 4-fold greater than liver and, in muscles, was not dependent upon CPT2. Together, these data suggest that dietary octanoate cannot rescue CPT2-deficient cardiac disease. These data also suggest the existence of tissue-specific mechanisms for octanoate oxidative metabolism, with liver being independent of free carnitine availability while cardiac and skeletal muscles depend on carnitine but not on CPT2.

中文翻译：

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辛酸在肝脏和肌肉中的代谢差异很大，不能挽救 CPT2 缺乏症的心肌病。

长链脂肪酸氧化经常在影响心脏的原发性和全身性代谢疾病中受损，因此在治疗上增加对通常次要的能量底物（如酮和中链脂肪酸）的依赖可能有益于心脏健康。然而，这种疗法的分子基础尚不完全清楚。在这里，我们探索了辛酸（一种被称为不受调节的线粒体能量底物的八碳中链脂肪酸）改善长链脂肪酸氧化缺陷心脏由于肉碱棕榈酰转移酶 2 缺失（Cpt2 ^{M-/ -}）。CPT2 将线粒体基质中的酰基肉碱转化为酰基辅酶A，用于氧化生物能量代谢。在 Cpt2 ^M-/-小鼠，高辛酸生酮饮食未能缓解心肌肥大、功能障碍和酰基肉碱积累，这表明这种替代底物不足以补偿能量供应。与这一结果一致，我们确定了肌肉和肝脏之间的主要代谢区别，其中心脏和骨骼肌线粒体不能氧化游离辛酸，但肝脏能够氧化游离辛酸。肝线粒体，但不是心脏或肌肉，高度表达中链酰基辅酶A合成酶，可能使辛酸活化以进行氧化和规避酰基肉碱穿梭。相反，辛酰肉碱被肝脏、骨骼肌和心脏氧化，心脏中的速率是肝脏的 4 倍，并且在肌肉中，不依赖于 CPT2。一起，这些数据表明，饮食中的辛酸不能挽救 CPT2 缺陷型心脏病。这些数据还表明存在辛酸氧化代谢的组织特异性机制，肝脏不依赖于游离肉碱的可用性，而心肌和骨骼肌依赖肉碱而不依赖于 CPT2。