Circadian clocks play an important role in lipid homeostasis, with impact on various metabolic diseases. Due to the central role of skeletal muscle in whole-body metabolism, we aimed at studying muscle lipid profiles in a temporal manner. Moreover, it has not been shown whether lipid oscillations in peripheral tissues are driven by diurnal cycles of rest–activity and food intake or are able to persist in vitro in a cell-autonomous manner. To address this, we investigated lipid profiles over 24 h in human skeletal muscle in vivo and in primary human myotubes cultured in vitro. Glycerolipids, glycerophospholipids, and sphingolipids exhibited diurnal oscillations, suggesting a widespread circadian impact on muscle lipid metabolism. Notably, peak levels of lipid accumulation were in phase coherence with core clock gene expression in vivo and in vitro. The percentage of oscillating lipid metabolites was comparable between muscle tissue and cultured myotubes, and temporal lipid profiles correlated with transcript profiles of genes implicated in their biosynthesis. Lipids enriched in the outer leaflet of the plasma membrane oscillated in a highly coordinated manner in vivo and in vitro. Lipid metabolite oscillations were strongly attenuated upon siRNA-mediated clock disruption in human primary myotubes. Taken together, our data suggest an essential role for endogenous cell-autonomous human skeletal muscle oscillators in regulating lipid metabolism independent of external synchronizers, such as physical activity or food intake.

中文翻译：

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脂质组学揭示了人体骨骼肌的昼夜脂质振荡在体外培养的细胞肌管中持续存在

昼夜节律钟在脂质体内平衡中起重要作用，对各种代谢性疾病有影响。由于骨骼肌在全身新陈代谢中的核心作用，我们旨在以时间方式研究肌肉脂质分布。此外，尚未显示出周围组织中的脂质振荡是由休息活动和食物摄入的昼夜周期驱动还是能够以细胞自主方式在体外持续存在。为了解决这个问题，我们调查了人体骨骼肌在体内和体外培养的原代人肌管中24小时内的脂质分布。甘油脂，甘油磷脂和鞘脂表现出昼夜振荡，表明其昼夜节律对肌肉脂质代谢具有广泛的影响。值得注意的是，体内和体外脂质积累的峰值水平与核心时钟基因表达具有相干性。在肌肉组织和培养的肌管之间，脂质脂质振荡产物的百分比相当，并且暂时脂质谱与涉及其生物合成的基因的转录谱相关。在体内和体外，富含质膜外小叶的脂质以高度协调的方式振荡。在人类原代肌管中，siRNA介导的时钟破坏后，脂质代谢产物的振荡会大大减弱。两者合计，我们的数据表明内源性细胞自主人类骨骼肌振荡器在独立于外部同步器（例如体育锻炼或食物摄入）而独立于调节脂质代谢中起着至关重要的作用。时态脂质谱与参与其生物合成的基因的转录谱相关。在体内和体外，富含质膜外小叶的脂质以高度协调的方式振荡。在人类原代肌管中，siRNA介导的时钟破坏后，脂质代谢产物的振荡会大大减弱。两者合计，我们的数据表明内源性细胞自主人类骨骼肌振荡器在独立于外部同步器（例如体育锻炼或食物摄入）而独立于调节脂质代谢中起着至关重要的作用。时态脂质谱与参与其生物合成的基因的转录谱相关。在体内和体外，富含质膜外小叶的脂质以高度协调的方式振荡。在人类原代肌管中，siRNA介导的时钟破坏后，脂质代谢产物的振荡会大大减弱。两者合计，我们的数据表明内源性细胞自主人类骨骼肌振荡器在独立于外部同步器（例如体育锻炼或食物摄入）而独立于调节脂质代谢中起着至关重要的作用。在人类原代肌管中，siRNA介导的时钟破坏后，脂质代谢产物的振荡会大大减弱。两者合计，我们的数据表明内源性细胞自主人类骨骼肌振荡器在独立于外部同步器（例如体育锻炼或食物摄入）而独立于调节脂质代谢中起着至关重要的作用。在人类原代肌管中，siRNA介导的时钟破坏后，脂质代谢产物的振荡会大大减弱。两者合计，我们的数据表明内源性细胞自主人类骨骼肌振荡器在独立于外部同步器（例如体育锻炼或食物摄入）而独立于调节脂质代谢中起着至关重要的作用。