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This Article Full Text Full Text (PDF) All Versions of this Article: 297/6/C1520    most recent ajpcell.00372.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lustgarten, M. S. Articles by Van Remmen, H. PubMed PubMed Citation Articles by Lustgarten, M. S. Articles by Van Remmen, H.

Cellular and Mitochondrial Metabolism

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

Departments of ¹Physiology, ²Cellular and Structural Biology, and ³Pathology, and ⁴Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas; ⁵Molecular and Integrative Physiology and Biomedical Engineering, University of Michigan, Ann Arbor, Michigan; and ⁶Molecular Gerontology-Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

Submitted 14 August 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, we bred mice expressing Cre recombinase driven by the promoter for the inhibitory subunit of troponin (TnIFast-iCre) 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. F₂-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.

muscle function; contractile function; oxidative damage; free radical