Regular exercise plays an important preventive and therapeutic role in oxidative stress-associated diseases such as diabetes and its complications. Thiol antioxidants including thioredoxin (TRX) and glutathione (GSH) have a crucial role in controlling cellular redox status. In this study, the effects of 8 wk of exercise training on brain TRX and GSH systems, and antioxidant enzymes were tested in rats with or without streptozotocin-induced diabetes. We found that in untrained animals, the levels of TRX-1 (TRX1) protein and activity, and thioredoxin-interacting protein (TXNip) were similar in diabetic and nondiabetic animals. Exercise training, however, increased TRX1 protein in nondiabetic animals without affecting TXNip levels, whereas diabetes inhibited the effect of training on TRX1 protein and also increased TXNip mRNA. In addition, the proportion of oxidized glutathione (GSSG) to total GSH was increased in animals with diabetes, indicating altered redox status and possibly increased oxidative stress. Glutathione peroxidase-1 (GPX1) levels were not affected by diabetes or exercise training, although diabetes increased total GPX activity. Both diabetes and exercise training decreased glutathione reductase (GRD) activity and cytosolic superoxide dismutase (Cu,Zn-SOD) levels. Nevertheless, diabetes or training had no effect on Cu,Zn-SOD mRNA, Mn-SOD protein, total SOD activity, or catalase mRNA, protein, or activity. Our findings suggest that exercise training increases TRX1 levels in brain without a concomitant rise in TXNip, and that experimental diabetes is associated with an incomplete TRX response to training. Increased oxidative stress may be both a cause and a consequence of perturbed antioxidant defenses in the diabetic brain.

In diabetes, defense systems against cellular stress are impaired. Heat shock proteins (HSPs) function primarily as molecular chaperones. Factors that raise tissue HSP levels may slow progression of diabetes and improve diabetic complications that also affect brain tissue. This study tested the effect of an 8-week exercise training on brain HSP response in rats with or without streptozotocin-induced diabetes (SID). In untrained animals, the HSP levels were not different between SID and non-diabetic groups. Endurance training, however, increased HSP72 and HSP90 protein in non-diabetic rats, whereas SID significantly decreased the effect of training on these HSPs. At the mRNA level, HSP60, HSP90 and GRP75 were increased due to training, whereas HSP72 mRNA was only increased in exercise-trained diabetic animals. Training or diabetes had no effect on protein carbonyl content, a marker of oxidative damage. Altogether, our findings suggest that endurance training increases HSP expression in the brain, and that experimental diabetes is associated with an incomplete HSP response at the protein level.

The sirtuin family of proteins consists of seven members in mammals (SirT1-T7). Sirtuins share NAD dependency for their enzymatic activity, but some show NAD-dependent deacetylase activity, others exhibit ADP ribosyltransferase activity or both. Sirtuins have gained considerable attention due to their impact as physiological targets for treating diseases associated with aging. Sirtuins interact with metabolic pathways and may serve as entry points for drugs. This review discusses the biology of sirtuins and their potential as mediators of caloric restriction and pharmacological targets. Reduced insulin sensitivity, mitochondrial dysfunction, and others are consequences of aging or secondary to physical inactivity. Moreover, understanding human energy metabolism through sirtuins may provide a novel approach to exercise physiology. Quercetin, a natural polyphenolic flavonoid that has been widely investigated for its other health benefits, may act as an inducer of SirT1. The benefits of quercetin for exercise performance may have implications for athletes and extended to disease prevention.

Thioredoxin (TRX) is a protein disulfide reductase that plays an important role in many thiol-dependent cellular reductive processes, antioxidant protection, and signal transduction. Moreover, TRX reduces and maintains the function of many proteins during oxidative stress, which is increased in diabetes. The authors recently reported that diabetes impairs brain redox status and TRX response to exercise training. As a continuation of their studies, they hypothesized that alpha-lipoic acid, a natural thiol antioxidant, has a favorable effect on the brain TRX and glutathione (GSH) system in diabetes. Streptozotocin-induced diabetes was used as a chronic model and exhaustive exercise as an acute model for disrupted redox balance. Half the diabetic and nondiabetic animals were subjected to a bout of exhaustive exercise after 8 wk with or without lipoic acid and analyzed for key thiol antioxidants. Lipoic acid neither altered diabetes-induced oxidative stress as assessed by the increased ratio of oxidized to total GSH nor had any impact on the antioxidant protein response to exercise. However, lipoic acid increased mRNA of TRX-interacting protein, an inhibitor of TRX-1, and glutaredoxin-1 in diabetes. Exercise increased TRX-1 mRNA in both diabetic and nondiabetic animals but had no effect on TRX-1 protein. Cytosolic superoxide dismutase mRNA was only increased in diabetes, whereas exercise increased the protein levels in nondiabetic animals. The findings suggest that exhaustive exercise induces mRNA of TRX-1 in the brain and that lipoic acid cannot prevent diabetes-induced disturbances in GSH homeostasis. Because lipoic acid increased TRX-interacting protein transcription in diabetes, high doses may impair TRX-1 homeostasis.