The Effect of Aerobic Exercise Training on Cerebrovascular HSP70, HSP90, INOS and ENOS Expression in Type 1 Diabetes

The purpose of this study was to determine the effect of exercise training alone and in a model of Type 1 Diabetes Mellitus (T1DM), on Heat Shock Protein (HSP) and Nitric Oxide Synthase (NOS) expression in entorhinal adjacent large and small cerebral vessels. Thirty-two rats were randomly allocated to four groups: control sedentary (C), control exercised (CX), diabetic sedentary (D) and diabetic exercised (DX). Exercise training incorporated 5 days/week on a motorized treadmill (27m/min; 6 degree incline; 1 hour) for 10 weeks. Exercise trained groups had significantly greater Hsp70 expression than their respective non-trained groups (p\u3c0.05) and this response was not blunted in T1DM animals. The inducible NOS (iNOS) expression was greater in diabetic sedentary when compared to all other groups (p\u3c0.001). Co-localization of protein with smooth muscle cells illustrates that all HSP and NOS signal content is localized to the smooth muscle area (SMA)

High intensity aerobic exercise training improves deficits of cardiovascular autonomic function in a rat model of type 1 diabetes mellitus with moderate hyperglycemia

© 2016 Kenneth N. Grisé et al. Indices of cardiovascular autonomic neuropathy (CAN) in experimental models of Type 1 diabetes mellitus (T1DM) are often contrary to clinical data. Here, we investigated whether a relatable insulin-treated model of T1DM would induce deficits in cardiovascular (CV) autonomic function more reflective of clinical results and if exercise training could prevent those deficits. Sixty-four rats were divided into four groups: sedentary control (C), sedentary T1DM (D), control exercise (CX), or T1DM exercise (DX). Diabetes was induced via multiple low-dose injections of streptozotocin and blood glucose was maintained at moderate hyperglycemia (9-17 mM) through insulin supplementation. Exercise training consisted of daily treadmill running for 10 weeks. Compared to C, D had blunted baroreflex sensitivity, increased vascular sympathetic tone, increased serum neuropeptide Y (NPY), and decreased intrinsic heart rate. In contrast, DX differed from D in all measures of CAN (except NPY), including heart rate variability. These findings demonstrate that this T1DM model elicits deficits and exercise-mediated improvements to CV autonomic function which are reflective of clinical T1DM

High-intensity endurance training results in faster vessel-specific rate of vasorelaxation in type 1 diabetic rats.

This study examined the effects of 6 weeks of moderate- (MD) and high-intensity endurance training (HD) and resistance training (RD) on the vasorelaxation responsiveness of the aorta, iliac, and femoral vessels in type 1 diabetic (D) rats. Vasorelaxation to acetylcholine was modeled as a mono-exponential function. A potential mediator of vasorelaxation, endothelial nitric oxide synthase (e-NOS) was determined by Western blots. Vessel lumen-to-wall ratios were calculated from H&E stains. The vasorelaxation time-constant (τ) (s) was smaller in control (C) (7.2 ± 3.7) compared to D (9.1 ± 4.4) and it was smaller in HD (5.4 ± 1.5) compared to C, D, RD (8.3 ± 3.7) and MD (8.7 ± 3.8) (p<0.05). The rate of vasorelaxation (% · s(-1)) was larger in HD (2.7 ± 1.2) compared to C (2.0 ± 1.2), D (2.0 ± 1.5), RD (2.0 ± 1.0), and MD (2.0 ± 1.2) (p<0.05). τ vasorelaxation was smaller in the femoral (6.9 ± 3.7) and iliac (6.9 ± 4.7) than the aorta (9.0 ± 5.0) (p<0.05). The rate of vasorelaxation was progressively larger from the femoral (3.1 ± 1.4) to the iliac (2.0 ± 0.9) and to the aorta (1.3 ± 0.5) (p<0.05). e-NOS content (% of positive control) was greater in HD (104 ± 90) compared to C (71 ± 64), D (85 ± 65), RD (69 ± 43), and MD (76 ± 44) (p<0.05). e-NOS normalized to lumen-to-wall ratio (% · mm(-1)) was larger in the femoral (11.7 ± 11.1) compared to the aorta (3.2 ± 1.9) (p<0.05). Although vasorelaxation responses were vessel-specific, high-intensity endurance training was the most effective exercise modality in restoring the diabetes-related loss of vascular responsiveness. Changes in the vasoresponsiveness seem to be endothelium-dependent as evidenced by the greater e-NOS content in HD and the greater normalized e-NOS content in the smaller vessels

The glucoregulatory response to high-intensity aerobic exercise following training in rats with insulin-treated type 1 diabetes mellitus

© 2016, National Research Council of Canada. All rights reserved. An acute bout of exercise elicits a rapid, potentially deleterious, reduction in blood glucose in patients with type 1 diabetes mellitus (T1DM). In the current study, we examined whether a 10-week aerobic training program could alleviate the rapid exercise-associated reduction in blood glucose through changes in the glucoregulatory hormonal response or increased hepatic glycogen storage in an insulin-treated rat model of T1DM. Thirty-two male Sprague-Dawley rats were divided evenly into 4 groups: non-T1DM sedentary (C) (n = 8), non-T1DM exercised (CX) (n = 8), T1DM sedentary (D) (n = 8), and T1DM exercised (DX) (n = 8). Exercise training consisted of treadmill running for 5 days/week (1 h, 27 m/min, 6% grade) for 10 weeks. T1DM was induced by multiple streptozotocin injections (20 mg/kg) followed by implantation of subcutaneous insulin pellets. At week 1, an acute exercise bout led to a significant reduction in blood glucose in DX (p \u3c 0.05), whereas CX exhibited an increase in blood glucose (p \u3c 0.05). During acute exercise, serum epinephrine was increased in both DX and CX (p \u3c 0.05), whereas serum glucagon was increased during recovery only in CX (p \u3c 0.01). Following aerobic training in DX, the exercise-mediated reduction in blood glucose remained; however, serum glucagon increased to the same extent as in CX (p \u3c 0.05). DX exhibited significantly less hepatic glycogen (p \u3c 0.001) despite elevations in glycogenic proteins in the liver (p \u3c 0.05). Elevated serum epinephrine and decreased hepatic adrenergic receptor expression were also evident in DX (p \u3c 0.05). In summary, despite aerobic training in DX, abrupt blood glucose reductions and hepatic glycogen deficiencies were evident. These data suggest that sympathetic overactivity may contribute to deficiencies in hepatic glycogen storage

Metabolic Profiling Reveals Aggravated Non-Alcoholic Steatohepatitis in High-Fat High-Cholesterol Diet-Fed Apolipoprotein E-Deficient Mice Lacking Ron Receptor Signaling

Non-alcoholic steatohepatitis (NASH) represents the progressive sub-disease of non-alcoholic fatty liver disease that causes chronic liver injury initiated and sustained by steatosis and necroinflammation. The Ron receptor is a tyrosine kinase of the Met proto-oncogene family that potentially has a beneficial role in adipose and liver-specific inflammatory responses, as well as glucose and lipid metabolism. Since its discovery two decades ago, the Ron receptor has been extensively investigated for its differential roles on inflammation and cancer. Previously, we showed that Ron expression on tissue-resident macrophages limits inflammatory macrophage activation and promotes a repair phenotype, which can retard the progression of NASH in a diet-induced mouse model. However, the metabolic consequences of Ron activation have not previously been investigated. Here, we explored the effects of Ron receptor activation on major metabolic pathways that underlie the development and progression of NASH. Mice lacking apolipoprotein E (ApoE KO) and double knockout (DKO) mice that lack ApoE and Ron were maintained on a high-fat high-cholesterol diet for 18 weeks. We observed that, in DKO mice, the loss of ligand-dependent Ron signaling aggravated key pathological features in steatohepatitis, including steatosis, inflammation, oxidation stress, and hepatocyte damage. Transcriptional programs positively regulating fatty acid (FA) synthesis and uptake were upregulated in the absence of Ron receptor signaling, whereas lipid disposal pathways were downregulated. Consistent with the deregulation of lipid metabolism pathways, the DKO animals exhibited increased accumulation of FAs in the liver and decreased level of bile acids. Altogether, ligand-dependent Ron receptor activation provides protection from the deregulation of major metabolic pathways that initiate and aggravate non-alcoholic steatohepatitis

e-NOS protein content and e-NOS content normalized to the lumen-to-wall-ratio for each vessel and group.

<p>Values are means ± (SD). D, diabetic animals; RD, resistance trained diabetic animals; MD, moderate intensity endurance trained diabetic animals; HD, high intensity endurance trained animals; n, number of animals; *significantly different from HD (p<0.05).</p

Time constant (τ) (A), calculated time delay (CTD) (B), and time-to-steady-state (C), responses for each vessel and group.

<p>Values are means ± (SD). D, diabetic animals; RD, resistance trained diabetic animals; MD, moderate intensity endurance trained diabetic animals; HD, high intensity endurance trained animals; *significantly different from HD (p<0.05); ^†significantly different from D (p<0.05).</p

Vasorelaxation kinetics parameters, percent vasorelaxation, and rate of vasorelaxation in the aorta, iliac, and femoral in control (C), diabetic (D), resistance training diabetic (RD), moderate (MD)- and high (HD)-intensity endurance training diabetic groups.

<p>Values are means ± (SD). C, control animals; D, diabetic animals; RD, resistance trained diabetic animals; MD, moderate intensity endurance trained diabetic animals; HD, high intensity endurance trained animals; n, number of animals; τ, time constant for the vasorelaxation response; CTD, calculated time delay for the vasorelaxation response; Time-to-steady-state, CTD +4 τ; Rate of vasorelaxation, percent vasorelaxation/time-to-steady-state; L-NAME, N^G-nitro-L-arginine methyl ester; SNP, sodium nitroprusside;</p>*<p>significantly different from HD (p<0.05);</p>†<p>significantly different from D (p<0.05);</p>#<p>femoral significantly different from aorta (p<0.05);</p>‡<p>femoral significantly different from iliac (p<0.05).</p>§<p>iliac significantly different from aorta (p<0.05).</p

Neuroprotective Role of the Ron Receptor Tyrosine Kinase Underlying Central Nervous System Inflammation in Health and Disease

Neurodegeneration is a critical problem in aging populations and is characterized by severe central nervous system (CNS) inflammation. Macrophages closely regulate inflammation in the CNS and periphery by taking on different activation states. The source of inflammation in many neurodegenerative diseases has been preliminarily linked to a decrease in the CNS M2 macrophage population and a subsequent increase in M1-mediated neuroinflammation. The Recepteur D’Origine Nantais (Ron) is a receptor tyrosine kinase expressed on tissue-resident macrophages including microglia. Activation of Ron by its ligand, macrophage-stimulating protein, attenuates obesity-mediated inflammation in the periphery. An in vivo deletion of the ligand binding domain of Ron (Ron−/−) promotes inflammatory (M1) and limits a reparative (M2) macrophage activation. However, whether or not this response influences CNS inflammation has not been determined. In this study, we demonstrate that in homeostasis Ron−/− mice developed an inflammatory CNS niche with increased tissue expression of M1-associated markers when compared to age-matched wild-type (WT) mice. Baseline metabolic analysis of CNS tissue indicates exacerbated levels of metabolic stress in Ron−/− CNS. In a disease model of multiple sclerosis, experimental autoimmune encephalomyelitis, Ron−/− mice exhibit higher disease severity when compared to WT mice associated with increased CNS tissue inflammation. In a model of diet-induced obesity (DIO), Ron−/− mice exhibit exacerbated CNS inflammation with decreased expression of the M2 marker Arginase-1 (Arg-1) and a robust increase in M1 markers compared to WT mice following 27 weeks of DIO. Collectively, these results illustrate that activation of Ron in the CNS could be a potential therapeutic approach to treating various grades of CNS inflammation underlying neurodegeneration