Overexpression of Skeletal Muscle Nrf2 Protects Against Aging‐Associated Dysfunction in Skeletal Muscle and Heart

The nuclear factor erythroid 2–related factor 2 (Nrf2) is a master transcription factor governing hundreds of genes coding proteins involved in anti-oxidation, anti-inflammation, detoxification, and metabolism. Using a model of tissue-specific deletion of the gene for Kelch Like ECH Associated Protein 1 (Keap1), an endogenous inhibitor of Nrf2, we previously found that Nrf2 overexpression upregulates over 100 proteins in skeletal muscle (SkM), which results in activation of endogenous antioxidant defenses and the enhancement of exercise capacity in adult mice. In addition, by employing a SkM-reporter mouse, where SkM exclusively expresses GFP while non-muscle tissues express td-Tomato, we demonstrated that SkM-derived extracellular vesicles (EVs) can be transferred from SkM to remote non-SkM tissues, including cardiomyocytes. Given the critical role of oxidative stress in the pathogenesis of sarcopenia and cardiac aging, we hypothesized that Keap1 KO can protect against aging-associated myopathy not only in SkM but also in myocardium via EV-mediated inter-organ antioxidant protein communication.