Evaluation of the effect of Exercise Trainings and CGRP receptor antagonist (BIBN 4096) on mitochondrial dynamic in the hippocampus of male Wistar rats.

BACKGROUND: Exercise training showed beneficial effects on brain. The purpose of the present study is to evaluate the effect of six weeks of high-intensity interval training (HIIT) and Endurance training (ET) with calcitonin gene-related peptide (CGRP) receptor antagonist on the expression of genes involved in mitochondrial dynamics and apoptosis in hippocampal tissue of male Wistar rats. METHODS: In this study, forty-two healthymale Wistar rats (8-week) were randomly divided into 6 groups (n = 7) as follow; 1) Control; 2) HIIT which performed 6 weeks of HIIT; 3) ET which performed 6 weeks of endurance training; 4) CGRPi received 10 mg/kg CGRP receptor antagonist every day at the last 2 weeks; 5) CGRPi-HIIT performed HIIT and received CGRP receptor antagonist; 6) CGRPi-ET performed ET and received CGRP receptor antagonist. Real-time PCR (2-ΔΔCT) and western blotting were employedto measure the expression of genes and protein, respectively. RESULTS: HIIT and ET significantly increased Bcl-2, Pgc-1α, Sirt3, and Nrf-1 gene expression in the hippocampal tissue (p < 0.05, p < 0.01, p < 0.01, and p < 0.001, respectively). ET-CGRPi and HIIT-CGRPi significantly increased Sirt3, Pgc-1α, and Nrf-1 gene expression compared to the control group (p < 0.05, p < 0.01, and p < 0.05, respectively). CONCLUSION: ET and HIIT-induced physiological alterations in the hippocampus. In fact, this modulation showed protective properties in the hippocampusvia up regulation of Bcl-2, Pgc-1α, Nrf-1, and Sirt3 gene expression. CGRPi did not cause gene or protein changes harmful to mitochondrial dynamic balance and apoptosis in the hippocampus of rats.

Therapeutic effects of the combination of moderate-intensity endurance training and MitoQ supplementation in rats with isoproterenol-induced myocardial injury: The role of mitochondrial fusion, fission, and mitophagy.

INTRODUCTION: Mitochondrial dysfunction causes myocardial disease. This study investigated the effects of MitoQ alone and in combination with moderate-intensity endurance training (EX) on cardiac function and content and mRNA expression of several proteins involved in mitochondrial quality control in isoproterenol (ISO)-induced heart injuries METHODS: Seven groups of CTL, ISO, ISO-EX, ISO-MitoQ-125, ISO-MitoQ-250, ISO-EX+MitoQ-125, and ISO-EX+MitoQ-250 were assigned. Rats were trained on a treadmill, and the MitoQ groups received MitoQ in drinking water for 8 weeks, starting one week after the induction of heart injury. Arterial pressure and cardiac function indices, mRNA expression, protein content, oxidant and antioxidant markers, fibrosis, and histopathological changes were assessed by physiograph, Real-Time PCR, immunofluorescence, calorimetry, Masson's trichrome, and H&E staining, respectively. RESULTS: The impacts of MitoQ-125, EX+MitoQ-125, and EX+MitoQ-250 on arterial pressure and left ventricular systolic pressure were higher than MitoQ-250 or EX alone. ± dp/dt max were higher in ISO-EX+MitoQ-125 and ISO-EX+MitoQ-250 than ISO-MitoQ-125 and ISO-MitoQ-250 groups, respectively. Histopathological scores and fibrosis decreased in ISO-EX, ISO-MitoQ-125, ISO-EX+MitoQ-125, and ISO-EX+MitoQ-250 groups. The restoration of MFN2, PINK-1, and FIS-1 changes was higher in ISO-EX+MitoQ-125 and ISO-EX+MitoQ-250 than ISO-EX, ISO-MitoQ-125 and ISO-MitoQ-250 groups. The expression of MFN2 and PINK-1 was lower in ISO-MitoQ-125 and ISO-EX+MitoQ-125 than ISO and CTL groups. The expression of FIS-1 in ISO-EX and ISO-EX+MitoQ-250 increased compared to CTL and ISO groups. MDA decreased in ISO-MitoQ-125 and ISO-EX+MitoQ-125 groups. CONCLUSION: Exercise and MitoQ combination have additive effects on cardiac function by modulating cardiac mitochondria quality. This study provided a possible therapy to treat heart injuries.

Endurance training and MitoQ supplementation improve spatial memory, VEGF expression, and neurogenic factors in hippocampal tissue of rats.

Background and Aim: The hippocampus has a key role in memory and learning, which means that this brain structure has high-energy demand. Accordingly, mitochondrial dysfunction in the hippocampus has deleterious effects on brain function. MitoQ is an antioxidant that accumulates selectively in mitochondria at high concentration. In this study, the effect of MitoQ alone and in combination with endurance training (ET) was investigated on spatial memory (distance, time, and number of passes in the target quarter), antioxidant status (superoxide dismutase [SOD] and glutathione peroxidase [GPx]), and neurogenic factor levels (vascular endothelial growth factor [VEGF] and brain-derived neurotrophic factor [BDNF]) in male Wistar rats. Methods: Rats were assigned to a control (CTL) group, ET group, ET+MitoQ group, and a MitoQ group. Rats were trained on a treadmill for 8 weeks, 5 days/week, and 50 min/day. MitoQ (250 µM daily) was administered through drinking water for 8 weeks. Spatial memory (Morris water maze test), gene expression (real-time PCR), protein expression (Western blotting), and antioxidants (ELISA method) were determined. Results: Distance and number of passes in the target quarter in the ET, MitoQ, and ET+MitoQ groups were higher than in the CTL group (P=0.001). MitoQ+ET had more impact on the abovementioned indices than MitoQ or ET alone. Simultaneous use of MitoQ and ET significantly increased gene and protein expression of VEGF (P=0.0001) and gene expression of BDNF (P=0.004) and Sestrin 2 (SESN2) (P=0.0001) in hippocampal tissue. The expression of VEGF (P=0.007) and SESN2 (P=0.001) was higher in the MitoQ group compared to the CTL group. Tissue GPx levels were increased following all three interventions (P≤0.013) compared to the CTL group while SOD levels remained unchanged in all groups. Conclusions: The combination of ET and MitoQ has additive effects on spatial memory in rats by modulating parameters that are involved in hippocampal neurogenesis. In addition, MitoQ may have positive effects on the antioxidant defense by improving GPx activity. Relevance for Patients: Considering the positive effects of MitoQ on improving the memory and the antioxidant defense, it seems that it can play a positive role in improving the diseases associated with memory loss in the long term, and ET along with this supplement can increase the possible positive effects.

Moderate Endurance Training and MitoQ Improve Cardiovascular Function, Oxidative Stress, and Inflammation in Hypertensive Individuals: The Role of miR-21 and miR-222: A Randomized, Double-Blind, Clinical Trial.

OBJECTIVE: Hypertension (HTN) is among the leading causes of myocardial infarction, stroke, and kidney disease. The MitoQ supplement is a mitochondrial-targeted antioxidant that attenuates the generation of reactive oxygen species (ROS). miRNAs play an essential role in the pathophysiology of HTN. Regular aerobic exercise is recommended to decrease the risk of cardiovascular disease. We aimed to evaluate the effects of MitoQ supplementation and moderate endurance training (ET), alone and in combination, on cardiac function, blood pressure, the circulatory levels of miRNA-21 and miRNA-222, and oxidative status in individuals with HTN. MATERIALS AND METHODS: In a double-blind, randomized clinical trial (except for ET group), 52 male hypertensive subjects (40-55 years old) were randomly divided into four groups (n=13): Placebo, MitoQ (20 mg/day, oral), ET (Cycle ergometer, moderate intensity, 40-60% VO2 peak, three sessions/week for six weeks), and MitoQ+ET. Cardiac echocardiography indices, serum oxidative and inflammation status, and miRNAs 21 and 222 were assessed before and after interventions. RESULTS: Left ventricular mass [effect size (ES): -6.3, 95% confidence interval (CI): -11.2 to -1.4] and end-systolic/ diastolic diameters significantly improved in the intervention groups (ES: -0.05, 95% CI: -0.11 to 0.00 and -0.09, 95% CI: -0.16 to -0.02). Total serum antioxidant capacity (TAC) increased (ES: 36.0, 95% CI: 26.1 to 45.8), and malondialdehyde (MDA) (ES: -0.43, 95% CI: -0.53 to -0.32), IL-6 (ES: -1.6, 95% CI: -1.98 to -1.25), miR-21 (ES: -0.48, 95% CI: -0.61 to -0.35), and miR-222 (ES: -0.31, 95% CI: -0.44 to -0.18) significantly decreased in response to ET, MitoQ, and their combination. CONCLUSION: MitoQ and ET, individually and more pronouncedly in combination, can improve cardiovascular health in people with high blood pressure (BP) by reducing inflammation and increasing antioxidant defense, in association with reduction in circulatory miR-21 and miR-222 levels (registration number: IRCT20190228042870N1).

The Effects of Six Weeks of Endurance Training and CGRP Inhibition on Nrf2 and AKT Expression in the Hippocampal Tissue of Male Wistar Rats.

Purpose: To study the effects of a six-week endurance training protocol and calcitonin gene-related peptide (CGRP) inhibition on the nuclear factor erythroid 2-related factor 2 (Nrf2) and protein kinase B (PKB) or AKT expression in the hippocampal tissue of male Wistar rats. Main Methods. Building on a controlled experimental design with a posttest, 28 healthy Wistar male rats were randomly assigned to four groups (n = 7 per group), including control, control+CGRP inhibition, endurance training, and endurance training+CGRP inhibition groups. The training groups were trained for six weeks. Rats in the CGRP inhibition group received CGRP receptor antagonist daily (0.25 mg/kg) via intravenous (IV) injection. The Nrf2 and AKT (PKB) expression was measured using the real-time PCR technique. Results: In the endurance training group, Nrf2 expression in the hippocampal tissue was increased significantly more than in other groups (P < 0.05). There was also a significant increase in the AKT expression in the endurance training group compared to the control group (P = 0.048) and in the endurance training+CGRP inhibition compared to the control group (P = 0.012). In addition, there was no significant relationship between AKT (PKB) and Nrf2 (r = -0.27, n = 28, P = 0.16). Conclusion: Endurance training alone has been able to increase Nrf2 and AKT (PKB) mRNA levels in the hippocampal tissue, considering that endurance training had no significant effect on AKT and Nrf2 expression after adding to CGRP inhibition.

Impact of aging on the work of breathing during exercise in healthy men.

This study examined the impact of aging on the elastic and resistive components of the work of breathing (Wb) during locomotor exercise at a given 1) ventilatory rate, 2) metabolic rate, and 3) operating lung volume. Eight healthy younger (25 ± 4 yr) and 8 older (72 ± 6 yr) participants performed incremental bicycle exercise, from which retrospective analyses identified similar ventilatory rates (approximately 40, 70, and 100 L·min-1), similar metabolic rates (V̇o2: approximately 1.2, 1.6, and 1.9 L·min-1), and similar lung volumes [inspiratory and expiratory reserve volumes (IRV/ERV: approximately 25/34%, 16/33%, and 13-34% of vital capacity]. Wb at each level was quantified by integrating the averaged esophageal pressure-volume loop, which was then partitioned into elastic and resistive components of inspiratory and expiratory work using the modified Campbell diagram. IRV was smaller in the older participants during exercise at ventilations of 70 and 100 L·min-1 and during exercise at the three metabolic rates (P < 0.05). Mainly because of a greater inspiratory elastic and resistive Wb in the older group (P < 0.05), total Wb was augmented by 40%-50% during exercise at matched ventilatory and matched metabolic rates. When examined during exercise evoking similar lung volumes, total Wb was not different between the groups (P = 0.86). Taken together, although aging exaggerates total Wb during locomotor exercise at a given ventilatory or a given metabolic rate, this difference is abolished during exercise at a given operating lung volume. These findings highlight the significance of operating lung volume in determining the age-related difference in Wb during locomotor exercise.NEW & NOTEWORTHY This study evaluated the impact of aging on the work of breathing (Wb) during locomotor exercise evoking similar ventilatory rates, metabolic rates, and operating lung volumes in young and older individuals. Mainly because of a greater inspiratory elastic and resistive Wb in older participants, total Wb was higher during exercise at any given ventilatory and metabolic rate with aging. However, this age-related difference was abolished during exercise evoking similar operating lung volumes in both age groups. These findings highlight the significance of lung volumes in determining the age-related difference in total Wb.

Effect of Combined Endurance Training and MitoQ on Cardiac Function and Serum Level of Antioxidants, NO, miR-126, and miR-27a in Hypertensive Individuals.

OBJECTIVES: Hypertension (HTN) is one of the most important risk factors for cardiovascular diseases. Despite advances in treatment and control of HTN, the prevalence of HTN is still increasing. MitoQ is a supplement that acts on mitochondria and attenuates reactive oxygen species (ROS), which plays an important role in cardiovascular health. miRNAs play an important role in the pathophysiology of HTN. We evaluated the effects of MitoQ supplementation and endurance training (ET), alone and in combination, on functional indices of the heart and serum levels of miR-126, miR-27a, antioxidants, and NO, in patients with HTN. METHODS: In a double-blind randomized clinical trial, 52 male participants (age 40-55 years) were randomly divided into four groups (n = 13) of placebo, MitoQ (20 mg/day, oral), ET (cycle ergometer, moderate intensity, 40-60% VO2 peak, heart rate 120-140 b/min, 45 min a day, three days/week for six weeks), and MitoQ+ET. Cardiac function indices were assessed by echocardiography before and after interventions. RESULTS: Systolic blood pressure (SBP) significantly decreased in all intervention groups (P < 0.001) while DBP (P < 0.01) and LV hypertrophy (P < 0.05) were significantly decreased only in the MitoQ+ET group. Serum levels of SOD, GPx, and NO and the level of miR-126 significantly increased in all treatment groups, while miR-27a reduced in the ET (P < 0.05) and MitoQ+ET (P < 0.01) groups. CONCLUSIONS: Compared to MitoQ and ET alone, their combination has more prominent improving effects on cardiac health and amelioration of BP in the patients with HTN. These effects are through miR-126 and miR-27a modulation and ameliorating mitochondrial ROS production.

Serum microRNA-33 levels in pre-diabetic and diabetic patients.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and abnormal insulin secretion. MicroRNAs are small, non-coding RNAs that are able to affect cell biological functions and act as biomarkers for some diseases such as DM. In current study, we measured serum miR-33 in three groups (n = 15) as follows; non-diabetic control, pre-diabetic, and DM patients. Real-time PCR method was used to quantify miR-33 expression. miR-33 expression was significantly increased in pre-diabetic subjects compared to other two groups (p < 0.001). FBS (p < 0.001), insulin (p < 0.001), HOMA-IR (p < 0.001), and TG (p = 0.026) were higher in diabetic subjects than the other two groups. In people that had high physical activity, the number of diabetic subjects were zero and most of them were in pre-diabetic group (p = 0.019). Serum miR-33 level significantly and positively correlated with pre-diabetic state (B = 2.67, p = 0.000), Sex (B = 1.03, p = 0.025), and FBS (B = 0.04, p = 0.036) and also miR-33 was significantly and negatively correlated with HOMA-IR (B = - 1.58, p = 0.04). These findings support the possible role of miR-33 to monitor pre-diabetes onset and progression. It needs to be evaluated in future studies with high number of participants to clarify its mechanism and diagnostic viability.