Sustained nutrient (fuel) excess, as occurs during obesity and diabetes, has been linked to increased inflammation, impaired mitochondrial homeostasis, lipotoxicity, and insulin resistance in skeletal muscle. Precisely how mitochondrial dysfunction is initiated and whether it contributes to insulin resistance in this tissue remains a poorly resolved issue. Herein, we examine the contribution that an increase in proinflammatory NFkB signalling makes towards regulation of mitochondrial bioenergetics, morphology, and dynamics and its impact upon insulin action in skeletal muscle cells subject to chronic fuel (glucose and palmitate) overloading. We show sustained nutrient excess of L6 myotubes promotes activation of the IKKβ-NFkB pathway (as judged by a six-fold increase in IL-6 mRNA expression; an NFkB target gene) and that this was associated with a marked reduction in mitochondrial respiratory capacity (>50%), a three-fold increase in mitochondrial fragmentation and 2.5-fold increase in mitophagy. Under these circumstances, we also noted a reduction in the mRNA and protein abundance of PGC1α and that of key mitochondrial components (SDHA, ANT-1, UCP3, and MFN2) as well as an increase in cellular ROS and impaired insulin action in myotubes. Strikingly, pharmacological or genetic repression of NFkB activity ameliorated disturbances in mitochondrial respiratory function/morphology, attenuated loss of SDHA, ANT-1, UCP3, and MFN2 and mitigated the increase in ROS and the associated reduction in myotube insulin sensitivity. Our findings indicate that sustained oversupply of metabolic fuel to skeletal muscle cells induces heightened NFkB signalling and that this serves as a critical driver for disturbances in mitochondrial function and morphology, redox status, and insulin signalling.

中文翻译：

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促炎性NFkB信号传导会响应细胞燃料超负荷而促进骨骼肌线粒体功能障碍。

肥胖症和糖尿病期间持续存在的营养物（燃料）过量与炎症增加，线粒体体内稳态受损，脂毒性和骨骼肌胰岛素抵抗有关。确切地说，线粒体功能障碍是如何引发的，以及它是否有助于组织中的胰岛素抵抗，仍然是一个难以解决的问题。本文中，我们研究了促炎性NFkB信号传导对线粒体生物能，形态和动力学调节的贡献及其对骨骼肌细胞中胰岛素作用的影响，骨骼肌细胞受慢性燃料（葡萄糖和棕榈酸酯）超负荷的影响。我们显示L6肌管持续营养过量会促进IKKβ-NFkB途径的激活（通过IL-6 mRNA表达增加六倍来判断；NFkB靶基因），并且与线粒体呼吸能力的显着降低（> 50％），线粒体碎片增加3倍，线粒体增加2.5倍有关。在这种情况下，我们还注意到PGC1α和关键线粒体成分（SDHA，ANT-1，UCP3和MFN2）的mRNA和蛋白质丰度降低，以及细胞ROS升高和肌管中胰岛素作用受损。令人惊讶的是，NFkB活性的药理或遗传抑制改善了线粒体呼吸功能/形态的紊乱，减轻了SDHA，ANT-1，UCP3和MFN2的损失，减轻了ROS的增加以及相关的肌管胰岛素敏感性降低。