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Am J Physiol Cell Physiol (September 23, 2009). doi:10.1152/ajpcell.00372.2009
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Research Article

Conditional knockout of MnSOD targeted to type IIB skeletal muscle fibers increases oxidative stress and is sufficient to alter aerobic exercise capacity

Michael Lustgarten, PhD,1 Youngmok Jang, PhD,1 Yuhong Liu,1 Florian Muller,1 Wenbo Qi,1 Mark Steinhelper,1 Susan Brooks, PhD,2 Lisa M. Larkin,2 Takahiko Shimizu,3 Takuji Shirasawa,3 Linda McManus,1 Arunabh Bhattacharya,1 Arlan Richardson,1 and Holly Van Remmen1,*

1University of Texas Health Science Center at San Antonio 2University of Michigan 3Tokyo Metro. Inst. Gerontol.

Submitted 14 August 2009 ; revised 15 September 2009 ; accepted in final form 22 September 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, mice expressing Cre recombinase driven by the promoter for the inhibitory subunit of troponin (TnIFast-iCre) were bred with mice containing a floxed Sod2 (Sod2fl/fl) allele. Manganese superoxide dismutase (MnSOD) activity was reduced by 82% in glycolytic (mainly type II) muscle fiber homogenates from young TnIFastCreSod2fl/fl mice. Furthermore, MnSOD content was reduced by 70% only in type IIB muscle fibers. Aconitase activity was decreased 56%, data that suggest elevated mitochondrial matrix superoxide. Mitochondrial superoxide release was elevated greater than two-fold by mitochondria isolated from glycolytic skeletal muscle in TnIFastCreSod2fl/fl mice. In contrast, the rate of mitochondrial hydrogen peroxide production was reduced by 33%, and only when respiring on complex II substrate. F2-isoprostanes were increased by 36% in tibialis anterior muscles isolated from TnIFastCreSod2fl/fl mice. Elevated glycolytic muscle-specific mitochondrial oxidative stress and damage in TnIFastCreSod2fl/fl mice was associated with a decreased ability of the extensor digitorus longus and gastrocnemius muscles to produce contractile force as a function of time, while force production by the soleus muscle was unaffected. TnIFastCreSod2fl/fl mice ran 55% less distance on a treadmill relative to wild type mice. Collectively, these data suggest that elevated mitochondrial oxidative stress and damage in glycolytic muscle fibers is sufficient to reduce contractile muscle function and aerobic exercise capacity.

type IIB skeletal muscle; MnSOD; oxidative stress; muscle function


* University of Texas Health Science Center at San Antonio vanremmen{at}uthscsa.edu






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