Low-intensity exercise in the prevention of cardiac insulin resistance-related inflammation and disturbances in NOS and MMP-9 regulation in fructose-fed ovariectomized rats

Abstract

Exercise is important nonpharmacological treatment for improvement of insulin sensitivity in menopause. However, its effect on menopausal cardiac insulin resistance is needing further research. We investigated protective effects of low-intensity exercise on cardiac insulin signaling, inflammation, regulation of nitric oxide synthase (NOS) and matrix metalloproteinase 9 (MMP-9) in ovariectomized (OVX) Wistar rats, submitted to 10% fructose solution for 9 weeks. OVX rats were divided into control, sedentary fructose, and exercise fructose groups. Measurements of physical and biochemical characteristics were carried out to evaluate metabolic syndrome development. Messenger RNA and protein levels and phosphorylation of cardiac insulin signaling molecules, endothelial and inducible NOS (eNOS and iNOS), p65 subunit of nuclear factor κB (NFκB), tumor necrosis factor α (TNF-α), suppressor of cytokine signaling 3 (SOCS3), and MMP-9 were analyzed. Fructose increased insulin level, homeostasis model assessment (HOMA) index, and visceral adipose tissue weight, while low-intensity exercise prevented insulin level and HOMA index increase. Fructose also decreased cardiac pAkt (Ser473), peNOS (Ser1177) and increased insulin receptor substrate 1 (IRS1) phosphorylation at Ser307, pNFκB (Ser276) and NFκB and MMP-9 content, without any effect on iNOS, protein-tyrosine phosphatase 1B, TNF-α, and SOCS3. Exercise prevented changes in pIRS1 (Ser307), pAkt (Ser473), peNOS (Ser1177), pNFκB (Ser276), and NFκB expression. In addition, exercise increased pIRS1 (Tyr632), pAkt (Thr308), and eNOS expression. Low-intensity exercise prevented cardiac insulin signaling disarrangement in fructose-fed OVX rats and therefore eNOS dysfunction, as well as pro-inflammatory signaling activation, without effect on tissue remodeling, suggesting physical training as a way to reduce cardiovascular risk.

The effects of low‐intensity exercise on cardiac glycogenesis and glycolysis in male and ovariectomized female rats on a fructose‐rich diet

“…As reported elsewhere (Stanišić et al, 2016;Stanisic et al, 2019), in this study, fructose overload led to the development of metabolic disturbances, including increased visceral adipose tissue, insulin concentration, and homeostasis model assessment index (HOMA) in both male and ovx female rats. However, in fructose-fed males, exercise managed to decrease visceral adiposity and insulin level and increase insulin sensitivity, while in females, it prevented insulin concentration and HOMA index increase.…”

“…The samples of the heart tissue derived from the same animals examined in our previous publications were used (Stanišić et al, 2016;Stanisic et al, 2019).…”

“…We demonstrated earlier that male and ovx female Wistar rats subjected to a high fructose diet for nine weeks are a relevant model of nutritionally induced cardiac insulin resistance and that lowintensity exercise can prevent cardiac insulin signaling deterioration (Stanišić et al, 2016;Stanisic et al, 2019). In this study, taking into account the fact that insulin regulates cardiac glucose transport (Shao & Tian, 2016), we hypothesized that a FRD affects cardiac glycolysis and glycogenesis in male and ovx female rats and that low-intensity exercise could be effective in the prevention of disturbances of key molecules of cardiac glucose metabolism (Figure 1).…”

Insulin Signaling In the Heart

“…HFD increases myocardial inflammation, promoting suppressor of cytokine signaling isoform 2 (SOCS2)-mediated serine phosphorylation of IRS1 (146). Fructose feeding increases transcriptional markers of inflammation and matrix remodeling in concert with decreased insulin signaling, changes in which are reversed by exercise training (147). Cardiac-released myokines (cardiokines) such as MG53 (aka TRIM 72) may impair systemic insulin action (148).…”

“…Altering dietary lipid composition could also reverse myocardial insulin resistance, as x3 FAs supplementation was shown to prevent myocardial insulin resistance in vitro under hyperinsulinemic conditions (166). Exercise activates AMPK in the heart (167) and reverses some of the defects in myocardial insulin signaling observed in the fructose-fed model of obesity and insulin resistance (147,168). Moreover, exercise overtraining-induced inflammation that reduces skeletal muscle insulin sensitivity continues to increase insulin signaling in heart (169).…”