Type II skeletal myofibers possess unique properties that potentiate mitochondrial H2O2 generation
Type II skeletal myofibers possess unique properties that potentiate mitochondrial H2O2 generation
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DOI：
10.1152/ajpcell.00402.2005
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发表时间：
2006-03-01
影响因子：
5.5
通讯作者：
Neufer, PD
中科院分区：
文献类型：
--
作者：
Anderson, EJ;Neufer, PD
线粒体功能障碍与许多骨骼肌病理有关，最明显的是衰老引起的萎缩和 II 型肌纤维的丧失。尽管氧自由基被认为是线粒体功能障碍的主要原因，但控制不同骨骼肌纤维类型中线粒体超氧化物产生的潜在因素尚不清楚。使用一种新颖的原位方法测量透化大鼠骨骼肌纤维束中 H2O2 的产生（超氧化物形成的指标），我们发现白色肌纤维（WG，主要是 IIB 型纤维）的线粒体自由基泄漏（H2O2 产生/O-2 消耗）比红色（RG，IIA 型）腓肠肌或比目鱼肌（I 型）肌纤维高出两到三倍（P < 0.05）。呼吸作用由复合物 I（丙酮酸 + 苹果酸）或复合物 II（琥珀酸）底物支持。在存在呼吸抑制剂的情况下，RG 和 WG 中复合物 I 和复合物 III 产生超氧化物的最大速率明显高于比目鱼肌，尽管 WG 肌纤维中的线粒体含量相似，少 50%。使用+/-外源性超氧化物歧化酶进行的重复实验揭示了WG与比目鱼肌和RG肌肉中超氧化物的拓扑和/或歧化的显着差异。当对线粒体含量进行标准化时，RG 和 WG 纤维的整体 H2O2 清除能力较低，而谷胱甘肽过氧化物酶活性（主要负责线粒体中 H2O2 的清除）在所有三种肌肉类型中都相似。这些发现表明，II 型肌纤维，特别是 IIB 型，具有增强线粒体超氧化物产生和/或释放的独特特性，为骨骼肌线粒体功能障碍的异质性发展提供了潜在机制。
Mitochondrial dysfunction is implicated in a number of skeletal muscle pathologies, most notably aging-induced atrophy and loss of type II myofibers. Although oxygen-derived free radicals are thought to be a primary cause of mitochondrial dysfunction, the underlying factors governing mitochondrial superoxide production in different skeletal myofiber types is unknown. Using a novel in situ approach to measure H2O2 production (indicator of superoxide formation) in permeabilized rat skeletal muscle fiber bundles, we found that mitochondrial free radical leak (H2O2 produced/O-2 consumed) is two- to threefold higher (P < 0.05) in white (WG, primarily type IIB fibers) than in red (RG, type IIA) gastrocnemius or soleus (type I) myofibers during basal respiration supported by complex I (pyruvate + malate) or complex II (succinate) substrates. In the presence of respiratory inhibitors, maximal rates of superoxide produced at both complex I and complex III are markedly higher in RG and WG than in soleus muscle despite similar to 50% less mitochondrial content in WG myofibers. Duplicate experiments conducted with +/- exogenous superoxide dismutase revealed striking differences in the topology and/or dismutation of superoxide in WG vs. soleus and RG muscle. When normalized for mitochondrial content, overall H2O2 scavenging capacity is lower in RG and WG fibers, whereas glutathione peroxidase activity, which is largely responsible for H2O2 removal in mitochondria, is similar in all three muscle types. These findings suggest that type II myofibers, particularly type IIB, possess unique properties that potentiate mitochondrial superoxide production and/or release, providing a potential mechanism for the heterogeneous development of mitochondrial dysfunction in skeletal muscle.