Metformin and caloric restriction induce an AMPK-dependent restoration of mitochondrial dysfunction in fibroblasts from Fibromyalgia patients
Metformin and caloric restriction induce an AMPK-dependent restoration of mitochondrial dysfunction in fibroblasts from Fibromyalgia patients
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DOI：
10.1016/j.bbadis.2015.03.005
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发表时间：
2015-07-01
影响因子：
6.2
通讯作者：
Cordero, Mario D.
中科院分区：
文献类型：
--
作者：
Alcocer-Gomez, Elisabet;Garrido-Maraver, Juan;Cordero, Mario D.
受损的AMPK与广泛的临床和病理状况相关，从肥胖、对运动或代谢综合征的反应改变到炎症、线粒体生物发生紊乱和对能量应激的反应缺陷。纤维肌痛（FM）是一种世界范围内扩散的肌肉骨骼慢性疼痛状况，影响高达5%的一般人群，包括所有上述病理生理状态。在这里，我们测试了来自FM患者的成纤维细胞中AMPK激活的参与。AMPK在FM患者的成纤维细胞中没有磷酸化，并且与线粒体生物合成减少、氧消耗减少、抗氧化酶表达水平降低和线粒体功能障碍相关。然而，线粒体DNA测序分析没有显示任何重要的改变，可以证明线粒体缺陷。在FM成纤维细胞中AMPK的激活在对中度氧化应激的反应中受损。相比之下，二甲双胍激活AMPK或与来自热量限制小鼠的血清孵育改善了FM成纤维细胞对中度氧化应激和线粒体代谢的反应。这些结果表明，AMPK在FM病理生理学中起着重要作用，并可能代表一个有价值的新的治疗靶点/策略的基础。此外，二甲双胍和热量限制可能是FM的一种有趣的治疗方法。(C)2015 Elsevier B. V.版权所有。
Impaired AMPK is associated with a wide spectrum of clinical and pathological conditions, ranging from obesity, altered responses to exercise or metabolic syndrome, to inflammation, disturbed mitochondrial biogenesis and defective response to energy stress. Fibromyalgia (FM) is a world-wide diffused musculoskeletal chronic pain condition that affects up to 5% of the general population and comprises all the above mentioned pathophysiological states. Here, we tested the involvement of AMPK activation in fibroblasts derived from FM patients. AMPK was not phosphorylated in fibroblasts from FM patients and was associated with decreased mitochondrial biogenesis, reduced oxygen consumption, decreased antioxidant enzymes expression levels and mitochondrial dysfunction. However, mtDNA sequencing analysis did not show any important alterations which could justify the mitochondrial defects. AMPK activation in FM fibroblast was impaired in response to moderate oxidative stress. In contrast, AMPK activation by metformin or incubation with serum from caloric restricted mice improved the response to moderate oxidative stress and mitochondrial metabolism in FM fibroblasts. These results suggest that AMPK plays an essential role in FM pathophysiology and could represent the basis for a valuable new therapeutic target/strategy. Furthermore, both metformin and caloric restriction could be an interesting therapeutic approach in FM. (C) 2015 Elsevier B.V. All rights reserved.