Conditional knockout of Mn-SOD targeted to type IIB skeletal muscle fibers increases oxidative stress and is sufficient to alter aerobic exercise capacity
Conditional knockout of Mn-SOD targeted to type IIB skeletal muscle fibers increases oxidative stress and is sufficient to alter aerobic exercise capacity
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DOI：
10.1152/ajpcell.00372.2009
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发表时间：
2009-12-01
影响因子：
5.5
通讯作者：
Van Remmen, Holly
中科院分区：
文献类型：
--
作者：
Lustgarten, Michael S.;Jang, Youngmok C.;Van Remmen, Holly
Lustgarten MS，Jang YC，Liu Y，Muller FL，Qi W，Steinhelper M，布鲁克斯SV，Larkin L，Shimizu T，Shirasawa T，McManus LM，Bhattacharya A，Richardson A，货车Remmen H.针对IIB型骨骼肌纤维的Mn-SOD的条件性敲除增加了氧化应激，并且足以改变有氧运动能力。美国生理学杂志细胞生理学297：C1520-C1532，2009年。首次发表于2009年9月23日; doi：10.1152/ajpcell.00372.2009。离体骨骼肌的体外研究表明，氧化应激限制收缩功能。线粒体是肌肉功能限制性氧化剂的潜在来源。为了检验骨骼肌特异性线粒体氧化应激足以限制肌肉功能的假设，我们将表达由肌钙蛋白抑制性亚基（TnIFastiCre）的启动子驱动的Cre重组酶的小鼠与含有floxed Sod 2（Sod 2（fl/fl））等位基因的小鼠进行了繁殖。Mn-SOD活性降低了82%的糖酵解（主要是II型）肌纤维匀浆从年轻TnIFastCreSod 2（fl/fl）小鼠。此外，Mn-SOD含量减少70%，只有在IIB型肌纤维。酶活性降低了56%，这表明线粒体基质超氧化物的增加。从TnIFastCreSod 2（fl/fl）小鼠的糖酵解骨骼肌中分离的线粒体使线粒体超氧化物释放升高两倍以上。与此相反，线粒体H2 O2的生产率降低了33%，只有在呼吸与复合物II基板。在从TnIFastCreSod 2（fl/fl）小鼠分离的胫骨前肌中，F-2-异前列烷增加了36%。TnIFastCreSod 2（fl/fl）小鼠中糖酵解肌肉特异性线粒体氧化应激和损伤升高与趾长伸肌和腓肠肌产生收缩力的能力降低相关，而比目鱼肌产生的力不受影响。TnIFastCreSod 2（fl/fl）小鼠在跑步机上跑的距离比野生型小鼠少55%。总的来说，这些数据表明，线粒体氧化应激和糖酵解肌纤维损伤的升高足以降低收缩肌肉功能和有氧运动能力。
Lustgarten MS, Jang YC, Liu Y, Muller FL, Qi W, Steinhelper M, Brooks SV, Larkin L, Shimizu T, Shirasawa T, McManus LM, Bhattacharya A, Richardson A, Van Remmen H. Conditional knockout of Mn-SOD targeted to type IIB skeletal muscle fibers increases oxidative stress and is sufficient to alter aerobic exercise capacity. Am J Physiol Cell Physiol 297: C1520-C1532, 2009. First published September 23, 2009; doi:10.1152/ajpcell.00372.2009.-In vitro studies of isolated skeletal muscle have shown that oxidative stress is limiting with respect to contractile function. Mitochondria are a potential source of muscle function-limiting oxidants. To test the hypothesis that skeletal muscle-specific mitochondrial oxidative stress is sufficient to limit muscle function, we bred mice expressing Cre recombinase driven by the promoter for the inhibitory subunit of troponin (TnIFastiCre) with mice containing a floxed Sod2 (Sod2(fl/fl)) allele. Mn-SOD activity was reduced by 82% in glycolytic (mainly type II) muscle fiber homogenates from young TnIFastCreSod2(fl/fl) mice. Furthermore, Mn-SOD content was reduced by 70% only in type IIB muscle fibers. Aconitase activity was decreased by 56%, which suggests an increase in mitochondrial matrix superoxide. Mitochondrial superoxide release was elevated more than twofold by mitochondria isolated from glycolytic skeletal muscle in TnIFastCreSod2(fl/fl) mice. In contrast, the rate of mitochondrial H2O2 production was reduced by 33%, and only during respiration with complex II substrate. F-2-isoprostanes were increased by 36% in tibialis anterior muscles isolated from TnIFastCreSod2(fl/fl) mice. Elevated glycolytic muscle-specific mitochondrial oxidative stress and damage in TnIFastCreSod2(fl/fl) mice were associated with a decreased ability of the extensor digitorum longus and gastrocnemius muscles to produce contractile force as a function of time, whereas force production by the soleus muscle was unaffected. TnIFastCreSod2(fl/fl) mice ran 55% less distance on a treadmill than wild-type mice. Collectively, these data suggest that elevated mitochondrial oxidative stress and damage in glycolytic muscle fibers are sufficient to reduce contractile muscle function and aerobic exercise capacity.