Conditional knockout of Mn-SOD targeted to type IIB skeletal muscle fibers increases oxidative stress and is sufficient to alter aerobic exercise capacity
- 1 December 2009
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 297 (6), C1520-C1532
- https://doi.org/10.1152/ajpcell.00372.2009
Abstract
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 ( TnIFast-iCre) with mice containing a floxed Sod2 ( Sod2fl/fl) allele. Mn-SOD activity was reduced by 82% in glycolytic (mainly type II) muscle fiber homogenates from young TnIFastCreSod2fl/flmice . 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 TnIFastCreSod2fl/flmice. In contrast, the rate of mitochondrial H2O2production was reduced by 33%, and only during respiration with complex II substrate. F2-isoprostanes were increased by 36% in tibialis anterior muscles isolated from TnIFastCreSod2fl/flmice. Elevated glycolytic muscle-specific mitochondrial oxidative stress and damage in TnIFastCreSod2fl/flmice 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. TnIFastCreSod2fl/flmice 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.Keywords
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