The Role of Skeletal Muscle Nrf2 on Cardiac Function in Mice

Abstract

Introduction: Excessive oxidant stress has been shown to damage cardiac tissue and result in impaired cardiac function. Animals with chronic heart failure (CHF) exhibit lower levels of antioxidant enzymes in many tissues including the heart, brain, and skeletal muscle (SkM). Nrf2 is a ubiquitous master transcription factor that regulates antioxidant proteins during enhanced oxidative stress. Earlier studies from this laboratory showed that exercise training was cardioprotective following ischemia reperfusion injury in mice. This protective effect was abrogated in mice in which the Nrf2 gene was deleted selectively in skeletal muscle. Given that skeletal muscle is approximately 40% of body weight and in light of recent findings on skeletal muscle derived extracellular vesicles, we sought to determine if up and downregulation of Nrf2 in skeletal muscle altered cardiac function. We hypothesized that skeletal muscle knockout of Nrf2 would impair cardiac function and the response to the beta 1 agonist dobutamine. Materials and Methods: Experiments were carried out in 37 males iMS-Keap1flox/flox and iMS-Nrf-2flox/flox (i.e. SkM specific) mice. Gene deletion was conditional upon the administration of the estrogen receptor agonist tamoxifen at 3 months of age; floxed mice given vehicle instead of tamoxifen were considered WT. The mice were assigned to 4 groups: Keap1 knockout (KO) (10), Keap1 WT (8), Nrf-2 KO (11), and Nrf-2 WT (8). Results: Keap1 deletion resulted in an increase in skeletal muscle hemoxygenase 1 (HO1) (p = 0.0286) while Nrf2 deletion resulted in a reduction in HO1 (p = 0.0286). However, there were no changes in the level of HO1 or other antioxidant proteins in the heart. Cardiac function was assessed with high frequency echocardiography (Vevo 3100). Systolic and diastolic function were analyzed. Up and downregulation of skeletal muscle Nrf2 did not evoke any change in either systolic or diastolic function. Conclusions: Previous studies have shown that Nrf2 upregulation salvaged cardiac function in mice subjected to either myocardial infarction or thoracic aortic constriction. Therefore, it may be that our lack of an effect of SkM specific Nrf2 manipulation is due to this study being carried out in normal animals and not in a disease setting such as CHF. In future work, this effect will be examined in mice with cardiac dysfunction. Supported by P0162222 and SURF from the APS This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.