Abstract
Mitochondrial oxidative stress is a complex phenomenon that is inherently tied to energy provision and is implicated in many metabolic disorders. Exercise training increases mitochondrial oxidative capacity in skeletal muscle yet it remains unclear if oxidative stress plays a role in regulating these adaptations. We demonstrate that the chronic elevation in mitochondrial oxidative stress present in Sod2 +/- mice impairs the functional and biochemical mitochondrial adaptations to exercise. Following exercise training Sod2 +/- mice fail to increase maximal work capacity, mitochondrial enzyme activity and mtDNA copy number, despite a normal augmentation of mitochondrial proteins. Additionally, exercised Sod2 +/- mice cannot compensate for their higher amount of basal mitochondrial oxidative damage and exhibit poor electron transport chain complex assembly that accounts for their compromised adaptation. Overall, these results demonstrate that chronic skeletal muscle mitochondrial oxidative stress does not impact exercise induced mitochondrial biogenesis, but impairs the resulting mitochondrial protein function and can limit metabolic plasticity.
Highlights
Mitochondria are a major source of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and complexes I, II and III can release the radical superoxide during electron transfer [1,2,3]
We found no differences between genotypes with regard to basal metabolic and behavioral parameters prior to or following the exercise training (Figure S1A-J)
Adenine nucleotide translocase 1 (ANT1) can facilitate uncoupling by allowing protons to leak across the mitochondrial inner membrane [35] and we found that ANT1 content was elevated in response to exercise training solely in Sod2+/- mice (Figure 2H)
Summary
Mitochondria are a major source of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and complexes I, II and III can release the radical superoxide during electron transfer [1,2,3]. Many health interventions that intend to augment mitochondrial content and metabolism in differentiated tissues in order to counter disease progression must contend with an environment of chronic mitochondrial oxidative stress (i.e. aging, obesity). Part of the controversy likely relates to variable uptake of these compounds in different tissues, non-specific cellular compartmentalization and complex dosage dependent prooxidant/anti-oxidant properties that are not clear in vivo (e.g. as with vitamin C, [15]). In relation to this ambiguity, the consumption of some antioxidant compounds may be harmful [16]
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