Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario, Canada.
Department of Physiological Sciences, Federal University of Santa Catarina, Florianopolis, Santa Catarina, Brazil.
J Physiol. 2020 Nov;598(21):4869-4885. doi: 10.1113/JP280032. Epub 2020 Aug 19.
Ketone bodies are proposed to represent an alternative fuel source driving energy production, particularly during exercise. Biologically, the extent to which mitochondria utilize ketone bodies compared to other substrates remains unknown. We demonstrate in vitro that maximal mitochondrial respiration supported by ketone bodies is low when compared to carbohydrate-derived substrates in the left ventricle and red gastrocnemius muscle from rodents, and in human skeletal muscle. When considering intramuscular concentrations of ketone bodies and the presence of other carbohydrate and lipid substrates, biological rates of mitochondrial respiration supported by ketone bodies are predicted to be minimal. At the mitochondrial level, it is therefore unlikely that ketone bodies are an important source for energy production in cardiac and skeletal muscle, particularly when other substrates are readily available.
Ketone bodies (KB) have recently gained popularity as an alternative fuel source to support mitochondrial oxidative phosphorylation and enhance exercise performance. However, given the low activity of ketolytic enzymes and potential inhibition from carbohydrate oxidation, it remains unknown if KBs can contribute to energy production. We therefore determined the ability of KBs (sodium dl-β-hydroxybutyrate, β-HB; lithium acetoacetate, AcAc) to stimulate in vitro mitochondrial respiration in the left ventricle (LV) and red gastrocnemius (RG) of rats, and in human vastus lateralis. Compared to pyruvate, the ability of KBs to maximally drive respiration was low in isolated mitochondria and permeabilized fibres (PmFb) from the LV (∼30-35% of pyruvate), RG (∼10-30%), and human vastus lateralis (∼2-10%). In PmFb, the concentration of KBs required to half-maximally drive respiration (LV: 889 µm β-HB, 801 µm AcAc; RG: 782 µm β-HB, 267 µm AcAc) were greater than KB content representative of the muscle microenvironment (∼100 µm). This would predict low rates (∼1-4% of pyruvate) of biological KB-supported respiration in the LV (8-14 pmol s mg ) and RG (3-6 pmol s mg ) at rest and following exercise. Moreover, KBs did not increase respiration in the presence of saturating pyruvate, submaximal pyruvate (100 µm) reduced the ability of physiological β-HB to drive respiration, and addition of other intracellular substrates (succinate + palmitoylcarnitine) decreased maximal KB-supported respiration. As a result, product inhibition is likely to limit KB oxidation. Altogether, the ability of KBs to drive mitochondrial respiration is minimal and they are likely to be outcompeted by other substrates, compromising their use as an important energy source.
酮体被认为是一种替代燃料来源，可以在运动期间提供能量。然而，关于线粒体利用酮体与其他底物的程度，生物学上仍不清楚。我们在体外证明，与来自啮齿动物的左心室和红色比目鱼肌的碳水化合物衍生底物相比，酮体支持的最大线粒体呼吸能力较低，在人类骨骼肌中也是如此。当考虑到肌肉内酮体的浓度和其他碳水化合物和脂质底物的存在时，酮体支持的生物线粒体呼吸速率预计会很低。因此，在心脏和骨骼肌中，酮体不太可能成为能量产生的重要来源，特别是在其他底物容易获得的情况下。
酮体（KB）最近作为一种替代燃料来源受到关注，可支持线粒体氧化磷酸化并增强运动表现。然而，鉴于酮裂解酶的活性低，以及碳水化合物氧化的潜在抑制作用，KB 是否能为能量产生做出贡献仍不清楚。因此，我们确定了 KB（dl-β-羟丁酸盐，β-HB；乙酰乙酸锂，AcAc）在大鼠左心室（LV）和红色比目鱼肌（RG）以及人类股外侧肌中刺激体外线粒体呼吸的能力。与丙酮酸相比，KB 最大程度地驱动呼吸的能力在分离的线粒体和透化纤维（PmFb）中较低（LV：30-35%的丙酮酸），RG（10-30%）和人类股外侧肌（2-10%）。在 PmFb 中，半最大程度地驱动呼吸所需的 KB 浓度（LV：889 µm β-HB，801 µm AcAc；RG：782 µm β-HB，267 µm AcAc）高于肌肉微环境中代表性的 KB 浓度（100 µm）。这将预测在休息和运动后，LV（8-14 pmol s mg ）和 RG（3-6 pmol s mg ）中生物 KB 支持的呼吸速率较低（~1-4%的丙酮酸）。此外，在饱和丙酮酸存在下，KB 不会增加呼吸，亚最大丙酮酸（100 µm）降低了生理β-HB 驱动呼吸的能力，并且添加其他细胞内底物（琥珀酸+棕榈酰肉碱）降低了最大 KB 支持的呼吸。因此，产物抑制可能会限制 KB 氧化。总之，KB 驱动线粒体呼吸的能力很低，它们很可能被其他底物竞争，从而使其无法成为重要的能源。
