The skeletal muscle plays a central role in glucose homeostasis through the uptake of glucose from the extracellular medium in response to insulin. A number of factors are known to disrupt the normal response to insulin leading to the emergence of insulin resistance (IR). Advanced age and a high-fat diet are factors that increase the susceptibility to IR, with lipid accumulation in the skeletal muscle being a key driver of this phenomenon. It is debated, however, whether lipid accumulation arises due to dietary lipid overload or from a decline of mitochondrial function. To gain insights into the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we combined lipidomics, proteomics, mitochondrial function analysis and computational modelling to investigate young and aged mice on a low- or high-fat diet (HFD). As expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals, glycolytic protein levels were reduced and less flexible to the diet. We conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their combined effects. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.

中文翻译：

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与年龄相关的胰岛素抵抗易感性是 CPT1B 下降和脂质超载共同作用的结果


骨骼肌响应胰岛素从细胞外介质中摄取葡萄糖，从而在葡萄糖稳态中发挥核心作用。已知许多因素会破坏对胰岛素的正常反应，从而导致胰岛素抵抗（IR）的出现。高龄和高脂肪饮食是增加 IR 易感性的因素，骨骼肌中的脂质积累是这种现象的关键驱动因素。然而，脂质积累是否是由于饮食脂质超载或线粒体功能下降引起的，仍存在争议。为了深入了解饮食和年龄在肌肉脂质和葡萄糖处理灵活性中的相互作用，我们结合脂质组学、蛋白质组学、线粒体功能分析和计算模型来研究低脂肪或高脂肪饮食 (HFD) 的年轻和老年小鼠。正如预期的那样，老年小鼠在接受 HFD 治疗时比年轻小鼠更容易受到 IR 的影响。 HFD 特别在老年小鼠中诱导肌内脂质积累，包括含有 C18:0 的神经酰胺和二酰基甘油。这反映在线粒体 β-氧化能力上，在年轻小鼠中，线粒体 β-氧化能力被 HFD 上调，但在年老小鼠中却没有。值得注意的是，大多数 β-氧化蛋白在两组中都被 HFD 上调，但肉碱棕榈酰转移酶 1B (CPT1B) 在老年动物中下降。计算模型将通量控制主要归因于 CPT1B，表明 CPT1B 驱动的 HFD 灵活性随着年龄的增长而丧失。最后，在年老的动物中，糖酵解蛋白水平降低，并且对饮食的灵活性较差。我们得出的结论是，肌内脂质积累和胰岛素敏感性降低并不是由于年龄相关的线粒体功能障碍或营养超负荷单独造成的，而是由它们的综合作用造成的。 此外，我们将 CPT1B 确定为抵消年龄依赖性肌内脂质积累并从而抵消 IR 的潜在靶点。