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1 Cellular & Molecular Physiology, Yale University, New Haven, CT, USA; John B. Pierce Laboratory, New Haven, CT, USA
2 John B. Pierce Laboratory, New Haven, CT, USA; Cellular & Molecular Physiology, Yale University, New Haven, CT, USA
* To whom correspondence should be addressed. E-mail: dneufer{at}jbpierce.org.
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/O2 consumed) is 2- to 3- fold higher (P<0.05) in white (WG, primarily type IIB fibers) than red gastrocnemius (RG, type IIA) 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 soleus despite ~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 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.
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