运动训练可诱导线粒体生物发生，而高脂饮食则增强线粒体利用长链和短链脂肪酸的能力

摘要(中文译文)

短链脂肪酸（SCFA）来源于过氧化物酶体代谢和肠道微生物群，已被提出作为支持骨骼肌等肝外组织线粒体氧化磷酸化（OXPHOS）的关键底物。然而，线粒体在多大程度上可以氧化SCFA（乙酸、丙酸和丁酸），以及运动训练和高脂肪饮食（HFD）调节这一过程的能力尚不清楚。在这里，我们发现SCFA支持的骨骼肌呼吸相对有限（18±6 nmol min-1 mg-1），仅占最大碳水化合物（丙酮酸：252±41 nmol min-1 mg-1。尽管容量较低，但HFD摄入后，线粒体氧化棕榈酰肉碱、乙酸盐和丁酸盐的内在能力增加（P<0.05：+50%），表明HFD会重新连接线粒体以优化脂质氧化。相比之下，运动训练阻止了这些HFD诱导的内在线粒体反应。尽管内在变化具有生物学相关性，但骨骼肌对代谢应激的适应也涉及线粒体生物合成和线粒体蛋白质组的扩展。蛋白质组学分析和柠檬酸合酶活性表明，尽管HFD独立地没有改变线粒体蛋白质丰度，但运动训练增加了线粒体蛋白质，在HFD存在的情况下，这种反应会增强。因此，尽管运动没有直接增强线粒体SCFA支持的呼吸，但HFD和运动的联合作用预测，由于线粒体丰度增加，SCFA氧化的整体能力更强。总的来说，尽管SCFA对骨骼肌线粒体呼吸的贡献最小，但HFD和运动的结合主要通过增加线粒体蛋白丰度而不是内在的线粒体重塑，协同增强了包括SCFA在内的多种底物的整体OXPHOS能力。关键点：过氧化物酶体和肠道来源的短链脂肪酸（SCFA）已被提出作为支持骨骼肌氧化磷酸化的替代代谢燃料来源。线粒体SCFA氧化的能力和适应性仍然未知。与碳水化合物（丙酮酸）和长链脂肪酸连接的底物相比，SCFA支持的线粒体呼吸是有限的（<15%）。高脂肪喂养增加了线粒体利用棕榈酰肉碱、醋酸盐和丁酸盐的内在能力，而4周的运动训练可以阻止这种作用。高脂肪饮食和运动训练相结合，以相加的方式增加了骨骼肌线粒体蛋白含量，提高了氧化能力和利用长链脂肪酸和超临界脂肪酸作为燃料来源的能力。

Abstract

Short-chain fatty acids (SCFAs), derived from peroxisomal metabolism and the gut microbiota, have been proposed as key substrates to support mitochondrial oxidative phosphorylation (OXPHOS) in extrahepatic tissues such as skeletal muscle. However, the extent to which mitochondria can oxidize SCFAs (acetate, propionate and butyrate) and the ability of exercise training and a high-fat diet (HFD) to modulate this process remains unclear. Here, we show that SCFA-supported respiration in skeletal muscle is relatively limited (18 ± 6 nmol min mg), accounting for only ∼7% of maximal carbohydrate (pyruvate: 252 ± 41 nmol min mg) and ∼14% of LCFA (palmitoylcarnitine)-linked respiration. Despite this low capacity, the intrinsic mitochondrial ability to oxidize palmitoylcarnitine, acetate and butyrate increased (P < 0.05: +50%) following HFD consumption, suggesting HFD rewires mitochondria to optimize lipid oxidation. By contrast, exercise training prevented these HFD-induced intrinsic mitochondrial responses. Although intrinsic changes are biologically relevant, skeletal muscle adaptation to metabolic stress also involves mitochondrial biogenesis and an expansion of the mitochondrial proteome. Proteomic analysis and citrate synthase activity revealed that, although HFD independently did not alter mitochondrial protein abundance, exercise training increased mitochondrial proteins, a response amplified in the presence of a HFD. Consequently, although exercise did not directly enhance mitochondrial SCFA-supported respiration, the combined effect of HFD and exercise predicted a greater overall capacity for SCFA oxidation because of increased mitochondrial abundance. Collectively, although SCFAs contribute minimally to mitochondrial respiration in skeletal muscle, combined HFD and exercise synergistically enhance overall OXPHOS capacity across diverse substrates, including SCFAs, primarily through increased mitochondrial protein abundance rather than intrinsic mitochondrial remodelling. KEY POINTS: Peroxisome and gut derived short-chain fatty acids (SCFA) have been proposed as an alternative metabolic fuel source to support skeletal muscle oxidative phosphorylation. The capacity and adaptability of mitochondrial SCFA oxidation remains unknown. SCFA-supported mitochondrial respiration is limited (<15%) compared to carbohydrate (pyruvate) and long-chain fatty acid linked substrates. High-fat feeding increased the intrinsic capacity of mitochondria to utilize palmitoylcarnitine, acetate and butyrate- effects prevented by 4 weeks of exercise training. Combined high-fat diet and exercise training increased skeletal muscle mitochondrial protein content in an additive manner, increasing oxidative capacity and ability to utilize both long- and SCFAs as a fuel source.

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