Two weeks of metformin treatment enhances mitochondrial respiration in skeletal muscle of AMPK kinase dead but not wild type mice.
Two weeks of metformin treatment enhances mitochondrial respiration in skeletal muscle of AMPK kinase dead but not wild type mice.
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DOI：
10.1371/journal.pone.0053533
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wojtaszewski JF
中科院分区：
文献类型：
--
作者：
Kristensen JM;Larsen S;Helge JW;Dela F;Wojtaszewski JF
二甲双胍被用作抗糖尿病药物。二甲双胍通过改善肝脏和骨骼肌中的胰岛素敏感性来改善胰岛素抵抗。据报道，2型糖尿病肌肉中线粒体含量减少，可能导致糖尿病肌肉胰岛素敏感性降低。二甲双胍作用背后的分子机制尚未完全阐明，但已报告在肌肉中抑制线粒体中的复合物I以及激活5′AMP活化蛋白激酶（AMPK）。此外，AMPK激活和二甲双胍治疗均与线粒体功能和生物发生的刺激相关。然而，尚未研究骨骼肌中的因果关系。我们假设体内二甲双胍治疗对骨骼肌线粒体功能和蛋白表达的潜在影响依赖于AMPK信号传导。我们通过对肌肉特异性激酶死亡的α2（KD）AMPK小鼠和野生型（WT）同窝小鼠进行为期两周的口服二甲双胍治疗来研究这一点。我们测量了线粒体呼吸和蛋白质活性以及参与线粒体碳水化合物和脂肪代谢和氧化磷酸化的关键酶的表达。与WT胫骨前肌相比，AMPK KD的线粒体呼吸、HAD和CS活性、PDH和复合物I-V以及细胞色素c蛋白表达均降低。令人惊讶的是，与WT小鼠相比，二甲双胍治疗仅增强AMPK KD小鼠的呼吸，从而挽救了呼吸缺陷。在WT或AMPK KD小鼠中，二甲双胍不影响蛋白质活性或表达。我们得出结论，两周的体内二甲双胍治疗增强了线粒体缺陷型AMPK KD小鼠的线粒体呼吸，但对WT小鼠没有增强作用。这种改善似乎与AMPK无关，也不涉及关键线粒体蛋白的变化。
Metformin is used as an anti-diabetic drug. Metformin ameliorates insulin resistance by improving insulin sensitivity in liver and skeletal muscle. Reduced mitochondrial content has been reported in type 2 diabetic muscles and it may contribute to decreased insulin sensitivity characteristic for diabetic muscles. The molecular mechanism behind the effect of metformin is not fully clarified but inhibition of complex I in the mitochondria and also activation of the 5′AMP activated protein kinase (AMPK) has been reported in muscle. Furthermore, both AMPK activation and metformin treatment have been associated with stimulation of mitochondrial function and biogenesis. However, a causal relationship in skeletal muscle has not been investigated. We hypothesized that potential effects of in vivo metformin treatment on mitochondrial function and protein expressions in skeletal muscle are dependent upon AMPK signaling. We investigated this by two weeks of oral metformin treatment of muscle specific kinase dead α2 (KD) AMPK mice and wild type (WT) littermates. We measured mitochondrial respiration and protein activity and expressions of key enzymes involved in mitochondrial carbohydrate and fat metabolism and oxidative phosphorylation. Mitochondrial respiration, HAD and CS activity, PDH and complex I-V and cytochrome c protein expression were all reduced in AMPK KD compared to WT tibialis anterior muscles. Surprisingly, metformin treatment only enhanced respiration in AMPK KD mice and thereby rescued the respiration defect compared to the WT mice. Metformin did not influence protein activities or expressions in either WT or AMPK KD mice. We conclude that two weeks of in vivo metformin treatment enhances mitochondrial respiration in the mitochondrial deficient AMPK KD but not WT mice. The improvement seems to be unrelated to AMPK, and does not involve changes in key mitochondrial proteins.
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影响因子：
4.3
作者：
Carvalho, Cristina;Correia, Sonia;Moreira, Paula I.
通讯作者：
Moreira, Paula I.
影响因子：
4.8
作者：
El-Mir, MY;Nogueira, V;Leverve, X
通讯作者：
Leverve, X
影响因子：
4.8
作者：
Garcia-Roves, Pablo M.;Osler, Megan E.;Zierath, Juleen R.
通讯作者：
Zierath, Juleen R.
影响因子：
4.8
作者：
Fryer, LGD;Parbu-Patel, A;Carling, D
通讯作者：
Carling, D
DOI：
10.1152/ajpendo.2001.281.6.e1340
发表时间：
2001-12-01
影响因子：
5.1
作者：
Bergeron, R;Ren, JM;Shulman, GI
通讯作者：
Shulman, GI