OP35 - Mitochondrial oxidative stress in skeletal muscle and cardiac aging

Abstract

Mitochondrial dysfunction plays an important role in many chronic diseases, including aging. However the role of oxidative stress in this dysfunction remains controversial. We tested whether mitochondrial oxidative stress underlies not only mitochondrial deficits, but also declines in performance of skeletal and cardiac muscle in aged mice. Direct manipulation of mitochondrial H 2 O 2 (mtH 2 O 2 ) production by lifelong overexpression of mitochondrial targeted catalase reduced mitochondrial deficits in aged skeletal muscle and protected against age-related declines in cardiac function. To test whether manipulating mitochondrial oxidative stress late in life could reverse deficits in aged skeletal muscle and heart we used a novel mitochondrial targeted peptide, SS-31, that interacts with cardiolipin on the inner mitochondrial membrane. SS-31 reduces mtH 2 O 2 production in dysfunctional aged mitochondria and improved glutathione redox status while not affecting young healthy mitochondria. Acute (1 hr) and 8 week treatment with SS-31 had similar effects on mitochondrial function and skeletal muscle performance. Both treatments reversed age-related declines in in vivo maximal mitochondrial ATP production and efficiency of oxidative phosphorylation (P/O) while increasing muscle fatigue resistance. Treatment for 8 weeks also reversed cardiac dysfunction, especially diastolic dysfunction. These improvements in skeletal muscle and cardiac function translated to improved treadmill endurance capacity in the aged mice. These results reveal a dynamic relationship between mitochondrial deficits and the redox environment of the cell that affects function in these tissues. To examine the mechanisms underlying this interaction we are examining the effect of manipulating mitochondrial oxidant production on the thiol redox proteome. Aging is associated with increased S-glutathionylation of the thiol proteome in aged skeletal muscle. Treatment with SS-31 partially reverses many of these age-related changes, including proteins involved in E-C coupling, muscle contraction, and protein quality control. These results demonstrate that mitochondrial oxidant production alters redox dependent post-translational modifications throughout the muscle thereby providing a potential mechanism linking mitochondrial oxidative stress to loss of muscle function with age. Furthermore, we demonstrate that reversing this mitochondrial oxidative stress can rapidly improve function highlighting the interaction between mitochondria and cellular redox environment as an attractive target to improve health in the elderly.