Mono- and Polyunsaturated Fatty Acids Counter Palmitate-Induced Mitochondrial Dysfunction in Rat Skeletal Muscle Cells.
Mono- and Polyunsaturated Fatty Acids Counter Palmitate-Induced Mitochondrial Dysfunction in Rat Skeletal Muscle Cells.
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DOI：
10.33594/000000282
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发表时间：
2020-10-01
期刊：
影响因子：
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通讯作者：
Hundal, Harinder S
中科院分区：
文献类型：
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作者：
Nisr, Raid B;Shah, Dinesh S;Hundal, Harinder S
背景/目的：肥胖时循环中饱和脂肪酸(SFA)浓度的持续升高，如棕榈酸酯(PA)，可导致慢性低度炎症状态，这种状态与骨骼肌等组织的代谢功能障碍有关，其特征是线粒体功能紊乱和活性氧(ROS)产生增加。相比之下，单不饱和脂肪酸(MUFAs，例如棕榈油酸，PO；油酸，OL)和某些多不饱和脂肪酸(PUFAs，例如亚油酸，LO)已被证明可以保护骨骼肌细胞免受SFAs诱导的一些有害代谢影响，尽管目前尚不清楚这种保护是否与改善线粒体生物学和功能改变以及骨骼肌细胞的氧化还原状态有关。本研究的目的是探讨这一问题。方法：大鼠骨骼(L6)肌管与SFA单独孵育或与MUFA(PO，OL)或PUFA(LO)共同孵育16h后，进行亚细胞分离、免疫印迹、固定/活细胞成像(用于评估线粒体形态和ROS)或实时线粒体呼吸分析。结果：L6肌管与PA或硬脂酸盐(SFA，C18：0)孵育，但不能诱导月桂酸酯(一种中链SFA，C12：0)诱导促炎NFkB信号的强烈增加，以IkBalk丢失和IL-6表达增加为判断标准。SFA诱导的促炎张力的增加与ROS(超氧化物歧化酶和过氧化氢)的产生增加以及与线粒体生物发生、呼吸和形态有关的蛋白质(即PGC1pha、SDHA、ANT1和Mfn2)的显著丢失有关。与这些变化相一致的是，PA导致线粒体网络的严重断裂和线粒体呼吸能力的显著降低。在PO、OL和LO单独孵育的肌管中，这些变化并不明显，这些MUFAs和PUFA不仅否定了PA的促炎作用，而且拮抗了PA持续供过于求导致的线粒体生物学和ROS产生的生化、形态和功能变化。结论：PO、OL和LO具有抗炎和抗氧化特性，并能显著改善SFA诱导的线粒体形态和功能障碍。这些观察结果可能对制定策略具有重要的营养意义，这些策略可能有助于限制肥胖导致的骨骼肌等组织的代谢功能障碍。
BACKGROUND/AIMS: Sustained increases in the circulating concentration of saturated fatty acids (SFAs, e.g. palmitate (PA), as seen during obesity, induces a chronic low grade inflammatory state that has been linked to metabolic dysfunction in tissues such as skeletal muscle that is characterized by disturbances in mitochondrial function and heightened production of reactive oxygen species (ROS). In contrast, monounsaturated (MUFAs, e.g. palmitoleate, PO; oleate, OL) and certain polyunsaturated (PUFAs, e.g. linoleate, LO) fatty acids have been shown to protect against some of the harmful metabolic effects induced by SFAs although it currently remains unknown whether this protection is associated with improved morphological and functional changes in mitochondrial biology and redox status in skeletal muscle cells. The aim of the present study was to investigate this issue.METHODS: Rat skeletal (L6) myotubes were subject to sustained 16h incubation with SFAs either alone or in combination with a MUFA (PO, OL) or PUFA (LO) prior to performing subcellular fractionation, immunoblotting, fixed/live cell imaging (for assessment of mitochondrial morphology and ROS) or analysis of real time mitochondrial respiration.RESULTS: Incubation of L6 myotubes with PA or stearate (SFA, C18:0) but not laurate (a medium chain SFA, C12:0) induced a robust increase in proinflammatory NFkB signaling as judged by loss of IkBalpha and increased expression of IL-6. This heightened SFA-induced proinflammatory tone was associated with increased production of ROS (superoxide and hydrogen peroxide) and significant loss in proteins involved in mitochondrial biogenesis, respiration and morphology (i.e. PGC1alpha, SDHA, ANT1 and MFN2). Consistent with these changes, PA induced profound fragmentation of the mitochondrial network and a marked reduction in mitochondrial respiratory capacity. These changes were not evident in myotubes incubated with PO, OL or LO alone, and, strikingly, these MUFAs and PUFA not only negated the proinflammatory action of PA, but antagonised the biochemical, morphological and functional changes in mitochondrial biology and ROS production induced in myotubes by the sustained oversupply of PA.CONCLUSION: Our findings indicate that PO, OL and LO exhibit anti-inflammatory and antioxidant characteristics and, significantly, they can ameliorate SFA-induced disturbances in mitochondrial form and function. These observations may have important nutritional implications in developing strategies that could potentially help limit obesity-induced metabolic dysfunction in tissues such as skeletal muscle.