Effects of high-intensity interval training (HIIT) on skeletal muscle atrophy, function, and myokine profile in diabetic myopathy.

PURPOSE: Diabetes is a metabolic disorder characterized by chronic hyperglycemia due to insulin deficiency and/or loss of its action. Diabetic myopathy causes functional limitations in diabetic patients. The beneficial effects of high-intensity interval training (HIIT) are widely reported. We have hypothesized that HIIT application would prevent the development of diabetic myopathy. METHODS: Male, Wistar albino rats (10 W) were randomly divided into four groups (1)Control(C), (2)Diabetes(DM), (3)Training(HIIT), and (4)Diabetes + Training(DM + HIIT). Streptozotocin(60 mg/kg) was injected for the induction of diabetes. The maximum exercise capacity(MEC) of animals was determined by an incremental load test. HIIT protocol (4 min 85-95 % MEC, 2 min 40-50 % MEC, 6 cycles, 5 days/week) was applied for 8 weeks. In the end, functional parameters, atrophy, and resistance to fatigue in soleus and EDL muscles were evaluated. IL-6, FNDC5, and myonectin levels were measured in EDL, soleus, and serum. RESULTS: We observed atrophy, fatigue sensitivity, and proinflammatory alterations (IL-6 increase) in the EDL samples due to diabetic myopathy which were not observed in the soleus samples. HIIT application prevented the aforementioned detrimental alterations. Both force-frequency response and parallelly the twitch amplitude increased significantly in the DM + HIIT group. Half relaxation time (DT50) increased in both exercising and sedentary diabetics. FNDC5 was significantly higher in the exercising animals in soleus samples. Myonectin was significantly higher in the soleus muscle only in the DM + HIIT group. CONCLUSION: Current findings show that diabetic myopathy develops earlier in glycolytic-fast-twitch fibers(EDL) than in oxidative-slow-twitch fibers(soleus). Furthermore, HIIT application prevents atrophy in skeletal muscle, increases resistance to fatigue, and has an anti-inflammatory effect. NEW FINDINGS: The current study analyzes the myokine profile and skeletal muscle function under the effect of diabetes HIIT-type exercise. We also measured maximal exercise capacity and tailored the exercise program individually according to the result. Diabetic myopathy is an important complication of diabetes yet still, it is not understood completely. Our results show that HIIT-type training would be beneficial in diabetic myopathy but further investigation is needed to understand the whole molecular mechanism.

Effects of aerobic exercise on lipopolysaccharide-induced experimental acute lung injury in the animal model of type 1 diabetes mellitus.

NEW FINDINGS: What is the central question of this study? We evaluated the effects of diabetes and exercise on lipopolysaccharide-induced acute lung injury. By providing a comprehensive analysis of redox status, blood gases and histological parameters, we aimed to contribute to the ongoing debate in the literature. What are the main findings and its importance? We demonstrated the preventive effect of exercise, but diabetes did not alter the severity of acute lung injury. ABSTRACT: Acute lung injury (ALI) is a life-threatening respiratory condition. Diabetes (DM) is a metabolic disease characterized by hyperglycaemia. There is an ongoing debate concerning whether there is a protective effect of diabetes in ALI. Exercise is a special type of physical activity that has numerous beneficial effects. The aim of our study was to investigate the effects of diabetes and exercise on the prognosis of ALI. Male Wistar albino rats were divided into two groups (sedentary and exercise). Both groups were divided into four subgroups: Control, ALI, DM, DM+ALI (n = 6 each). Diabetes was induced by injection of streptozotocin (50 mg/kg i.p.). The maximal exercise capacity was determined with the incremental load test. Animals were exercised on a treadmill for 45 min at 70% of maximal exercise capacity, 5 days a week for 12 weeks. Acute lung injury was induced by intratracheal injection of lipopolysaccharide (100 µg/100 g body weight) 24 h before the end of the experiment. We performed arterial blood gas analysis. Redox status was measured in both plasma and lung tissue. Malondialdehyde and 8-hydroxy-2'-deoxyguanosine levels were measured in lung tissue. Lung tissue was evaluated histologically. Acute lung injury caused significant damage in the lung tissue, which was verified histologically, with an increase in oxidative stress parameters. Exercise prevented the lung damage induced by ALI and reduced oxidative stress in the lung tissue. Diabetes did not alter the magnitude of damage done by ALI. Exercise showed a protective effect against DM and ALI in rats. The effect of DM was insignificant for the prognosis of ALI.

Possible Adaptation of the Adrenal Gland Hsp72 Expression to Hypoxic Stress.

Akin, Senay, Metin Bastug, Ridvan Colak, Hakan Ficicilar, Betul Simten Saglam, Nazan S. Kosar, and Haydar Demirel. Possible adaptation of the adrenal gland Hsp72 expression to hypoxic stress. High Alt Med Biol. 22:293-299, 2021. Background: Adrenal glands play a central role in the general response to stress and controlling wholebody homeostasis. One of the most severe environmental stresses encountered by high-altitude climbers is hypoxia. Since the 72 kDa heat shock protein (Hsp72) has a critical role in cellular homeostasis, regulation of Hsp72 in adrenal glands seems to be crucial for maintaining cellular integrity of the gland and sustaining an adequate whole-body stress response in a hypoxic environment. Therefore, this study investigated if 15 days of hypoxia results in the induction of Hsp72 in adrenal glands. In addition, we examined whether heat treatment had any effect on adrenal Hsp72 expression to hypoxia, as cellular and systemic physiological cross-adaptation was suggested between heat stress and hypoxic stress. Materials and Methods: Male 4-month-old Wistar rats were randomly assigned to one of the four experimental groups (n = 8 each group): (1) control (C), (2) heat treatment (15H), (3) heat treatment and 15 days of normobaric hypoxia (15HHp), and (4) 15 days of normobaric hypoxia (15Hp). Three one-hour heat treatment sessions at 41°C were applied on the first two days before hypoxic exposure and on the day 7. Hypoxic exposure was consisting of normobaric hypoxia containing 9.7% O2. Results: Fifteen days of hypoxia did not increase the adrenal Hsp72 levels (p = 0.99). Furthermore, when hypoxia was added to the heat treatment, heat-related increases in adrenal Hsp72 levels disappeared. Adrenal weight to body weight ratio was not different among groups (p = 0.11). Plasma corticosterone levels were significantly lower in all experimental groups compared with control (p < 0.05), and addition of hypoxia resulted in further significant reduction of the plasma corticosterone levels (C > 15H>15HHp >15Hp; p < 0.05). Conclusions: These data demonstrate the adaptation of the adrenal gland to 15-day chronic normobaric hypoxic stress as well as possible cross-adaptation between heat and hypoxic stress in the adrenal gland.

Aerobic exercise has an anxiolytic effect on streptozotocin­induced diabetic rats.

Diabetes is a metabolic disorder characterized by hyperglycemia and impaired insulin secretion or action. Psychological comorbidities, such as depression and anxiety, are more common in people with diabetes. Exercise results in anxiolytic effects, as demonstrated in numerous studies. This study aims to evaluate potential anxiolytic effects of aerobic exercise in streptozotocin (STZ)­induced diabetes. Male Wistar albino rats (n=40) were randomly divided into four groups of control, exercise, diabetes, and diabetes + exercise. Diabetes was induced with a single i.p. injection of STZ. The incremental load test was applied to exercise groups to determine maximal exercise capacity. Rats exercised on a treadmill at 70% of their maximal capacity for 45 min, five days per week for 12 weeks. On the day after the last exercise session the open field test and elevated plus maze test were carried out. Diabetes caused an increase in anxiety level, reflected in stretch­attend posture, self­grooming behaviors, and freezing time, with no significant changes for other behavioral parameters. Training normalized diabetes­induced deteriorations and also induced a significant anxiolytic effect both on diabetic and non­diabetic rats. This effect was observed for all behavioral parameters. The results of the open field test and elevated plus maze were consistent. The current results demonstrated a slight increase in anxiety with diabetes and a prominent anxiolytic effect of aerobic exercise. Considering the conflicting results in exercise­anxiety studies, this study hig hlights the importance of individually designed exercise protocols.

Effects of exercise training on anxiety in diabetic rats.

Diabetes mellitus (DM) is a common health problem, which manifests itself with chronic hyperglycemia and impaired insulin action. The prevalence of anxiety disorders tends to be high in the diabetic population. Exercise has a well-known anxiolytic effect, also demonstrated on rodents, but the effect of exercise on the DM-induced anxiety is still unknown. Female, Wistar albino rats were randomly divided into four groups (n=8) (C; EX; DM; DM+EX). DM was induced by injection (i.p.; 50 mg/kg) of Streptozotocin (STZ). Rats exercised in moderate intensity on the treadmill (15m/min; 5°; 30 min) for 5 weeks. Anxiety-like behavior (ALB) was evaluated by Open field test (OFT) and Elevated Plus Maze (EPM). According to OFT, central time and central entry have increased with in EX but not in DM+EX. There was no difference between C and DM. Central latency time didn't differ among groups. Unsupported rearing increased in both EX and DM+EX. There was no significant decrease in DM. Freezing time was significantly increased in the DM group. Exercise training reduced freezing time both in diabetic and non-diabetic animals. EPM results were similar. Time spent in open arm was increased significantly in exercise groups compared to their sedentary matches, and freezing time data were also parallel to OFT. Our study revealed that diabetes had shown an anxiogenic effect, which was not severe, and it only manifested itself on some behavioral parameters. Exercise training was reduced anxiety-like behavior both in diabetic and non-diabetic rats. However, because of the nature of exercise studies, it is hard to separate the anxiolytic effect of exercise from the alteration of locomotion.

Intermittent hypoxia induces beneficial cardiovascular remodeling in left ventricular function of type 1 diabetic rat.

OBJECTIVE: Depressed mechanical activity is a marked complication in diabetics. Hypoxia has properties for novel diagnostic and therapeutic strategies, while intermittent hypoxia (IH) provides early functional and histologic remodeling, including some cardio benefits in early hemodynamic alterations with histologic remodeling and delayed changes in peripheral vasoreactivity. Therefore, we aimed to examine whether IH application presents a cardioprotective effect, via stabilization of hypoxia-inducible factor (HIF) in streptozotocin (STZ)-induced diabetic rat heart. METHODS: Male 10-week-old Wistar rats were randomly assigned as control group (C), IH group, (STZ)-induced diabetic group (DM) and IH applied DM group (DM+IH). Diabetes duration was kept 6 weeks and IH groups were exposed to hypobaric hypoxia at about 70 kPa (including ~14% PO2; 6 h/day for 6-weeks). RESULTS: Depressed left ventricular developed pressure (LVDP) and prolonged contraction and relaxation of Langendorff-perfused hearts, as well as increased total oxidative status from streptozotocin (STZ)-induced diabetic rats were markedly prevented with IH application. IH application induced significant increase in protein expression levels of both HIF-1α and vascular endothelial growth factor (VEGF), in both control and diabetic rat hearts, whereas there were significant decreases in the protein levels of prolyl-4 hydroxylase domain enzymes, PHD2, and PHD3 in diabetic hearts. Furthermore, IH application induced marked increases in protein levels of matrix metalloproteinases, MMP-2 and MMP-9 and capillary density in left ventricle of diabetic rats. CONCLUSION: Overall, we presented how IH application has a beneficial cardiovascular remodeling effect in left ventricular function of diabetic rats, at most, via affecting increased oxidative stress and HIF-VEGF related angiogenesis, providing information on hyperglycemia associated new targets and therapeutic strategies.

Effect of intermittent hypoxia on the cardiac HIF-1/VEGF pathway in experimental type 1 diabetes mellitus.

OBJECTIVE: High altitude and hypoxic preconditioning have cardioprotective effects by increasing coronary vascularity, reducing post-ischemic injury, and improving cardiac function. Our purpose was to examine if intermittent hypoxia treatment has any restoring effects related to the possible role of the HIF-1/VEGF pathway on diabetic cardiomyopathy. METHODS: Wistar Albino male rats (n=34) were divided into four groups: control (C), intermittent hypoxia (IH), diabetes mellitus (DM), and diabetes mellitus plus intermittent hypoxia (DM+IH). Following a streptozotocin (STZ) injection (50 mg/kg, i.p.), blood glucose levels of 250 mg/dL and above were considered as DM. IH and DM+IH groups were exposed to hypoxia 6 h/day for 42 days at a pressure corresponding to 3000 m altitude. Twenty-four hours after the IH protocol, hearts were excised. Hematoxylin and eosin-stained apical parts of the left ventricles were evaluated. Hypoxia inducible factor-1 (HIF-1), vascular endothelial growth factor 164 (VEGF164), and VEGF188 polymerase chain reaction products were run in agarose gel electrophoresis. Band density analysis of UV camera images was performed using Image J. The data were compared by one-way ANOVA, repeated measures two-way ANOVA, and the Kruskal-Wallis test. RESULTS: The percent weight change was lower in the DM group than in the controls (p=0.004). The tissue injury was the highest in the DM group and the least in the IH group. Diabetes decreased, whereas the IH treatment increased the vascularity. A decrease was observed in the VEGF188 mRNA levels in the DM+IH group compared with the C group, but there were no difference in HIF-1α and VEGF164 mRNA levels between the groups. CONCLUSION: The IH treatment restored the diabetic effects on the heart by reducing tissue injury and increasing the capillarity without transcriptional changes in HIF-1/VEGF correspondingly.

The effects of acute and intermittent hypoxia on the expressions of HIF-1α and VEGF in the left and right ventricles of the rabbit heart.

OBJECTIVE: Hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) are involved in signaling mechanisms of cellular responses to hypoxia. These factors have been investigated in tissue samples by simulating different altitudes by changing the percentage of oxygen. We aimed first to evaluate the effect of normobaric, systemic hypoxia (11% O2) on HIF-1α and VEGF mRNA levels in the heart muscle; secondly, to compare the levels of HIF-1α and VEGF mRNA in the left and right ventricle muscles. METHODS: In this experimental study, 33 New Zealand male rabbits were assigned to control, acute hypoxia (4 hours) and intermittent hypoxia (4 hours/day for 14 days) groups (n=11/group). Total RNA was isolated from right and left ventricles of the heart. The expressions of HIF-1α and VEGF mRNAs were investigated by using Reverse Transcription Polymerase Chain Reaction (RT-PCR) method. The obtained data were compared by using ANOVA and paired t-test. RESULTS: The results indicated that left ventricle VEGF mRNA expressions in both acute and intermittent hypoxia groups (1.08 ± 0.15 and 1.03 ± 0.19, respectively) were higher than that in the control group (0.88 ± 0.15) (p=0.03). Hypoxia treatments did not significantly alter HIF-1α mRNA in both ventricles (p=0.60 and p=0.51 for left and right ventricles, respectively). CONCLUSION: Since systemic hypoxia results in induction of VEGF mRNA up-regulation only in left ventricle, it could be related to its higher metabolic activity and oxygen utilization. Hypoxia induced changes in the expression of HIF-1α mRNA may not be the only determining factor for HIF-1/VEGF pathway induction or the observed VEGF induction could be through other hypoxia sensitive pathways.

Doppler ultrasound evaluation of the structural and hemodynamic changes in the brachial artery following two different exercise protocols.

PURPOSE: Examine the effects of incremental and submaximal exercise on structural and hemodynamic changes in the brachial artery flow parameters using Doppler ultrasonography. MATERIALS AND METHODS: Twenty four healthy sedentary males (aged 19.54+/-0.59) performed submaximal (15 minutes heart rate to 75% maximal) and incremental (workload was increased 20W every 3 minutes until exhaustion) exercises by upper extremity ergometer. Before and after exercises the brachial artery diameter, peak systolic maximum velocity (Vmax), end-diastolic minimum velocity (Vmin) and time-averaged mean flow velocity (Vmean), volume blood flow and flow waveform patterns were recorded in a controlled environment. RESULTS: The diameter of the brachial artery, flow velocities, and blood flow increased significantly after each exercise protocol (p < 0.001). The Vmax (p < 0.05), Vmean (p < 0.01), and volume blood flow (p < 0.01) after the incremental exercise were significantly higher than those measured after the submaximal exercise. However, no significant differences were noted between the two exercise protocols when arterial diameters and Vmin were concerned. The flow pattern was monophasic in all subjects after incremental exercise. Nevertheless, the flow pattern remained triphasic in two of the subjects after submaximal exercise. CONCLUSION: Blood flow velocities played important role in hemodynamic mechanism than conduit arterial diameter during arm exercises. Changes in conduit artery diameter did not significantly contribute to blood flow increase during high and moderate intensity exercises. There is minimal variation in waveform shapes of normal individuals after exercise. Doppler ultrasonography proved a practical tool in the studies of the dynamic responses of blood flow and vascular resistance during rest and exercises.