Redox stress resilience in aging skeletal muscle

University Of Washington, Seattle WA

Investigators

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Abstract

PROJECT SUMMARY/ABSTRACT Aging is associated with impaired stress resilience defined as a loss of the ability of cells, organs, and organisms to adapt to physiological or pathological stressors. Evidence suggests that this loss of resilience arises before any overt pathology, and eventually contributes to the loss of function, disease, and death. However, the cellular mechanisms that drive this process are poorly understood. For cells to adapt to environmental and endogenous stressors they need to be able to communicate the stress signal through signal transduction mechanisms. However, for transient stress signals to be effective, they should be low under resting conditions. The transcription factor Nrf2 activates early changes in gene expression to enhance redox and energetic adaptations in response to acute redox stress associated with muscle contraction. In healthy individuals this leads to an adaptive response to restore redox balance and increased cellular resilience to future stresses. Nrf2 is chronically activated under basal conditions and has an attenuated response to muscle contraction in human aged skeletal muscle. In addition, aging is associated with elevated reversible oxidation of the thiol proteome, a primary signal transduction mechanism driving redox adaptation, and that reducing mitochondrial redox stress restores the thiol proteome to that found in young. Here we test the hypothesis that mitochondrial redox stress in aging muscle is the chronic low-level stress that impairs the signal transduction communication in the cell underlying the impaired redox stress response to muscle contraction. This research uses skeletal muscle contraction as a model to generate new insights into the molecular mechanisms underlying reduced resilience with age. Aim 1 tests whether increasing mitochondrial redox stress is sufficient to drive declining muscle function and adaptive stress response signaling to acute muscle contraction by characterizing a novel SOD2 Knockdown mouse model and layering this knockdown to measure redox stress response signaling. Aim 2 tests whether decreasing mitochondrial or cytoplasmic redox stress is sufficient to restore adaptive stress response signaling to acute muscle contraction by treating young and old wild type mice as well as mice iSOD2 KD mice with mitoTEMPO or TEMPO as mitochondrial targeted antioxidant vs a non targeted antioxidant. Results from the proposed experiments will significantly impact the field by elucidating redox stress response signaling in aging and age-related muscle/mitochondrial dysfunction. These results will have clear clinical significance as there are already several mitochondrially targeted pharmacological compounds that are redox active and can be tested in humans.