Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats.
Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats.
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DOI：
10.1016/j.freeradbiomed.2010.06.022
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发表时间：
2010-09-15
影响因子：
7.4
通讯作者：
Neufer, P. Darrell
中科院分区：
文献类型：
--
作者：
Kane, Daniel A.;Anderson, Ethan J.;Price, Jesse W., III;Woodlief, Tracey L.;Lin, Chien-Te;Bikman, Benjamin T.;Cortright, Ronald N.;Neufer, P. Darrell
二甲双胍是一种广泛用于治疗2型糖尿病的处方药，尽管尚未确定其细胞作用机制。为了确定体内二甲双胍治疗是否会改变骨骼肌的线粒体功能，我们测量了用二甲双胍治疗4周的瘦型和肥胖型Zucker大鼠（fa/fa）皂素渗透肌纤维的呼吸O2通量和H2O2排放。琥珀酸盐和棕榈酰肉碱支持的呼吸作用使未经治疗的肥胖大鼠肌纤维中H2O2的排放率比瘦大鼠高2倍，表明肥胖相关的线粒体氧化剂排放电位增加。在改善血糖控制的同时，二甲双胍治疗将肥胖大鼠肌肉中的H2O2排放量降低到接近或低于瘦大鼠在琥珀酸盐和棕榈酰肉碱支持呼吸时所观察到的水平。令人惊讶的是，二甲双胍治疗并没有影响肥胖或瘦肉大鼠肌肉的基础或最大耗氧量。体外剂量反应实验表明，二甲双胍抑制复合体I-linked H2O2排放的浓度比抑制呼吸O2通量所需的浓度低2个数量级。这些发现表明，治疗浓度的二甲双胍通过阻断反向电子流使线粒体H2O2排放正常化，而不影响骨骼肌的正向电子流或呼吸O2通量。
Metformin is a widely prescribed drug for treatment of type 2 diabetes, although no cellular mechanism of action has been established. To determine whether in vivo metformin treatment alters mitochondrial function in skeletal muscle, respiratory O2 flux and H2O2 emission were measured in saponin-permeabilized myofibers from lean and obese (fa/fa) Zucker rats treated for 4 wks with metformin. Succinate- and palmitoyl-carnitine- supported respiration generated >2-fold higher rates of H2O2 emission in myofibers from untreated obese versus lean rats, indicative of an obesity-associated increased mitochondrial oxidant emitting potential. In conjunction with improved glycemic control, metformin treatment reduced H2O2 emission in muscle from obese rats to rates near or below those observed in lean rats during both succinate- and palmitoyl-carnitine- supported respiration. Surprisingly, metformin treatment did not affect basal or maximal rates of O2 consumption in muscle from obese or lean rats. Ex vivo dose-response experiments revealed that metformin inhibits complex I-linked H2O2 emission at a concentration ∼2 orders of magnitude lower than that required to inhibit respiratory O2 flux. These findings suggest that therapeutic concentrations of metformin normalize mitochondrial H2O2 emission by blocking reverse electron flow without affecting forward electron flow or respiratory O2 flux in skeletal muscle.
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影响因子：
8
作者：
Roesen, Peter;Wiernsperger, Nicolas F.
通讯作者：
Wiernsperger, Nicolas F.
影响因子：
7.7
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作者：
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通讯作者：
Neufer, P. Darrell