Novel role for thioredoxin reductase‐2 in mitochondrial redox adaptations to obesogenic diet and exercise in heart and skeletal muscle

Abstract

Key points• For reasons not completely understood, obesogenic high-fat, high-sucrose (HFHS) diets and exercise training both increase free fatty acid utilization and chronic oxidative stress, yet the former is deleterious to cardiovascular/metabolic health, whereas the latter is beneficial.• Here, we report that the heart shows decreased mitochondrial H 2 O 2 (mH 2 O 2 ) generation following HFHS diet, while skeletal muscle shows increased mH 2 O 2 , and uncover a novel role for thioredoxin reductase-2 (TxnRd2) underlying these differences.• We also show that TxnRd2 is critical to controlling mH 2 O 2 levels during mitochondrial fatty acid oxidation, especially following exercise training in skeletal muscle.• These findings are important in that they illustrate how the heart and skeletal muscle have contrasting adaptations in antioxidant capacity in response to HFHS diet, and uncover a new role for TxnRd2 in the overall control of mH 2 O 2 in these organs with HFHS diet and exercise training.Abstract Increased fatty acid availability and oxidative stress are physiological consequences of exercise (Ex) and a high-fat, high-sugar (HFHS) diet. Despite these similarities, the global effects of Ex are beneficial, whereas HFHS diets are largely deleterious to the cardiovascular system. The reasons for this disparity are multifactorial and incompletely understood. We hypothesized that differences in redox adaptations following HFHS diet in comparison to exercise may underlie this disparity, particularly in mitochondria. Our objective in this study was to determine mechanisms by which heart and skeletal muscle (red gastrocnemius, RG) mitochondria experience differential redox adaptations to 12 weeks of HFHS diet and/or exercise training (Ex) in rats. Surprisingly, both HFHS feeding and Ex led to contrasting effects in heart and RG, in that mitochondrial H 2 O 2 decreased in heart but increased in RG following both HFHS diet and Ex, in comparison to sedentary animals fed a control diet. These differences were determined to be due largely to increased antioxidant/anti-inflammatory enzymes in the heart following the HFHS diet, which did not occur in RG. Specifically, upregulation of mitochondrial thioredoxin reductase-2 occurred with both HFHS and Ex in the heart, but only with Ex in RG, and systematic evaluation of this enzyme revealed that it is critical for suppressing mitochondrial H 2 O 2 during fatty acid oxidation. These findings are novel and important in that they illustrate the unique ability of the heart to adapt to oxidative stress imposed by HFHS diet, in part through upregulation of K. H. Fisher-Wellman and T. A. Mattox contributed equally to this study.

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…Increased protein levels of cardiac TrxR2 have been previously observed in mice on a high‐fat, high‐sugar diet (Fisher‐Wellman et al. 2013). In that study, the authors also uncovered the critical role played by this enzyme in suppressing mitochondrial H 2 O 2 emission, specifically during fatty acid oxidation (Fisher‐Wellman et al.…”

“…In that study, the authors also uncovered the critical role played by this enzyme in suppressing mitochondrial H 2 O 2 emission, specifically during fatty acid oxidation (Fisher‐Wellman et al. 2013). …”

Exercise training promotes cardioprotection through oxygen-sparing action in high fat-fed mice

“…Long-term endurance exercise may potentially reduce ROS production due to systemic effects (improved insulin signaling, reduced inflammatory status, alteration of plasma lipids, and reduced activity of the reninangiotensin system), which may dampen the activation of ROS-producing enzymes. In addition, exercise training has also been reported to improve endogenous antioxidant capacity of the heart (17,20).…”

Metabolic Alterations Induce Oxidative Stress in Diabetic and Failing Hearts: Different Pathways, Same Outcome

“…In this model, the increased concentration of H 2 O 2 induces the activation of c-Jun N-terminal kinase, which promotes the phosphorylation of the transcription factor family FOXO, leading to catalase overexpression (73). The capacity of rat hearts to counteract the oxidative stress caused by a chronic high-fat/ high-sugar diet by upregulating thioredoxin reductase-2 has been recently shown, although the signaling involved in this mechanism was not investigated (27). Conversely, other authors found an increased expression of the thioredoxin endogenous inhibitor named thioredoxin interacting protein, and therefore reduced anti-oxidant defenses, after hyperglycemia in patients with diabetes and in rodents with type I and II diabetes (16).…”