High-intensity interval training ameliorate diabetes-induced disturbances in Alzheimer's-related factors in the hippocampus through adiponectin signaling

doi:10.21203/rs.3.rs-1736887/v1

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Research Article

High-intensity interval training ameliorate diabetes-induced disturbances in Alzheimer's-related factors in the hippocampus through adiponectin signaling

https://doi.org/10.21203/rs.3.rs-1736887/v1

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published 06 Mar, 2023

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Objectives: Alzheimer’s disease (AD) is closely related to type 2 diabetes (T2D). This study investigated the impact of High-intensity interval training (HIIT) on diabetes-induced disturbances in AD-related factors (including AMP-activated protein kinase (AMPK), Glycogen synthase kinase-3β (GSK3β), and Tau protein) in the hippocampus, with the main focus on adiponectin signaling.

Methods: 40 male Wistar rats at the age of 8 weekd were randomly assigned to four groups: control (Con), type 2 diabetes (T2D), HIIT (Ex), and type 2 diabetes + HIIT (T2D+Ex). T2D was induced by high-fat diet plus a single dose of Streptozotocin (STZ). Rats in Ex and T2D+Ex groups performed eight weeks of HIIT (running at 80-95% of Vmax, 4-10 intervals). Insulin and adiponectin levels in serum and hippocampus were measured along with hippocampal expression of insulin and adiponectin receptors, AMPK, GSK3β, and Tau. Homeostasis model assessment for Insulin Resistance (HOMA-IR), Homeostasis model assessment for Insulin Resistance Beta (HOMA-β), and quantitative insulin sensitivity check index (QUICKI) were calculated to assess insulin resistance and sensitivity.

Results: T2D decreased insulin and adiponectin levels in serum and hippocampus as well as the hippocampal levels of insulin and adiponectin receptors and AMKP but increased GSK3β and Tau in the hippocampus. HIIT reversed diabetes-induced impairments and consequently decreased Tau accumulation in the hippocampus of diabetic rats. HOMA-IR, HOMA-β, and QUICKI were improved in Ex and T2D+Ex groups.

Conclusion: Overall, our results confirmed that T2D has undesirable effects on the levels of some Alzheimer's-related factors in the hippocampus and HIIT could ameliorate these impairments in the hippocampus.

HIIT

Type 2 diabetes

Alzheimer’s disease

Hippocampus

Adiponectin

Sedentary lifestyles and increased tendency towards high-calorie and high-fat foods contribute to obesity [1] which is a risk factor for many diseases, including diabetes and cardiovascular disease. Diabetes is considered a metabolic disease that disrupts fat metabolism, increases adipose tissue (especially visceral), and causes glucose intolerance [2]. Associated usually with obesity, type 2 diabetes (T2D) is a disease in which the body does not respond to insulin normally, resulting in insulin resistance (IR) [1]. In addition to IR, diabetes can also disrupt adipokines production and secretion [3]. Adipokines are cytokines secreted by adipose tissue acting at autocrine/paracrine and endocrine levels. Adipokines have a role in regulating glucose and lipid metabolism, energy homeostasis, healthy behavior, insulin sensitivity, inflammation, immune system function, fat accumulation, vascular function, coagulation, and cognitive function. Evidence suggests that obesity and T2D can lead to Alzheimer's disease (AD) and cognitive disorders by disrupting adipokines functions [4]. AD is a progressive neurological disease and the most common type of dementia that causes significant damage to memory. Today, the number of dementia patients is estimated to be around 55 million worldwide, which will reach more than 131 million by 2050 [5]. 98% of people with AD suffer from one or more common diseases such as obesity and diabetes. Type 2 diabetes increases the risk of AD by about 1.6 times [6].

Adiponectin is an adiopkine that appears to mediate the cross-talk between adipose tissue and the central nervous system and considered as leading player in diabetes-induced AD [7]. Two adiponectin receptors, AdipoR1 and AdipoR2, have been identified in the brain. Based on the available evidence, adiponectin crosses the blood-brain barrier and binds to its receptors to activate cellular pathways, including insulin metabolism, mitochondrial biogenesis, and oxidative stress through AMP-activated protein kinase (AMPK) [7]. On the other hand, phosphorylation of p38-mitogen-activated protein kinases (p38-MAPK) stimulates neurogenesis through Glycogen synthase kinase-3β (GSK3β). In addition, there is a cross-talk between the AMPK and GSK-3β signaling pathways in which GSK-3β suppresses AMPK [7].

Adiponectin function in the central nervous system and in relation to AD has not yet been fully understood. However, because IR is commonly seen in early AD (hence called type 3 diabetes [8]), adiponectin might be a vital player in AD [9]. Adiponectin levels have been reported to increase [10], decrease [11], and in some cases, remain unchanged in AD [12]. To compensate for the increase in IR in the central nervous system, plasma adiponectin levels increase to stimulate the decreased activity of insulin receptors (i.e. a compensatory response). However, after crossing the blood-brain barrier and activating AMPK and p53-MAPK cascades, adiponectin increases the phosphorylated and toxic form of Tau protein, which leads to neuronal and synaptic cell death. Therefore, both positive and negative role is imaginable for adiponectin in AD [13].

Exercise effectively counteracts various metabolic problems, age-related loss of function, and physiological issues. Various studies have shown that different modalities of exercise such as treadmill [14–16], voluntary exercise [17–19], and swimming [20] are effective in AD and T2D diseases. Among all interventions, exercise could be used as a preventive strategy, does not have side effects, and has many positive physiological and psychological effects [21]. Regular exercise training could control dysglycemia, and hyperinsulinemia, increase insulin sensitivity, decrease body fat, and decrease blood pressure [22]. Exercise effects on metabolic disorders could be mediated through adiponectin [23]. Research has also shown that adiponectin role in T2D and AD is remarkable [13] and can be considered a link between the two diseases. Thus, exercise could be a preferred choice for preventing T2D induced AD. However, the therapeutic effect of exercise shows a dose-response pattern meaning that training variables should be manipulated carefully to reach the desirable adaption. It has been shown that adiponectin response to exercise is intensity-dependent, with high-intensity interval training (HIIT) as the most effective one. It has been demonstrated that 12 weeks of HIIT increased adiponectin levels and insulin sensitivity more than the same amount of moderate-intensity in obese individuals [24]. In addition, Martinez et al. [25] showed that while obesity leads to a decrease in adiponectin, this decrease was more inhibited in the HIIT group than in the continuous training group. This study investigated the effect of eight-week HIIT on adiponectin signaling and AMPK, GSK3β, and Tau protein in hippocampus of male rats with T2D.

Animal care

In the present study, we purchased 40 eight-week-old male Wistar rats with an average weight of 200 g from the animal farm of Kerman University of Medical Sciences (KUMS) and kept them at 23 ± 2°C and a 12:12 dark-light cycle in special polycarbonate cages. All animals had free access to water and food. The Ethics committee of KUMS approved the study protocol prior to any experiments being carried out (Ethics Approval Code: IR.KMU.REC.1399.503).

After being habituated to the laboratory environment, the animals were randomly assigned to four groups (n = 7 in each group): control (Con), type 2 diabetes (T2D), exercise (Ex), and type 2 diabetes + exercise (T2D + Ex). The Ex and T2D + Ex groups performed eight weeks of HIIT.

Induction of diabetes

T2D + Ex and T2D groups were fed a high-fat diet (HFD) for two months (Table 1). After two months, the animals fasted for 12 hours, and a single dose of 35 mg/kg streptozotocin (STZ) was injected intraperitoneally. Animal blood glucose was measured three days after STZ injection using a glucometer. Animals with fasting blood glucose (FBG) above 300 mg/dl were considered diabetic and included in the study [26].

Table 1

Regular and high-fat diet ingredients
Diet ingredients	Fat	Carbohydrate	Protein	Fiber	Minerals	Vitamins
Regular diet	10%	70%	20%	50 g	50 g	3 g
High-fat diet	60%	20%	20%	50 g	50 g	3 g

Exercise protocol

All animals were familiarized with the motorized treadmill. They ran on the treadmill at 8 m/min with an incline of 0%, 10 min/day for five consecutive days prior to the experiments. The Ex and T2D + Ex groups performed an incremental running test to determine their maximum speed (V_max). They ran for 2 minutes at a 6 m/min speed, and every 2 minutes, 2 m/min was added to the speed until they became exhausted. The last min tolerated speed was considered as V_max. Finally, the training protocol was carried out five times a week for eight weeks (29). Rats’ V_max was measured every two weeks, and the new V_max was used to calculate relative speed in the next two weeks (Table 2).

Table 2

High-intensity interval training (HIIT) protocol
week	Frequency	intervals	High-intensity interval duration (min)	Low-intensity interval duration (min)	High-intensity interval velocity (Vmax)	Low-intensity interval velocity (Vmax)	Total exercise time in a session (min)
1	5	4	2	80	1	50	12
2	5	4	2	80	1	50	12
3	5	6	2	85	1	50	18
4	5	6	2	85	1	50	21
5	5	8	2	90	1	50	24
6	5	8	2	90	1	50	24
7	5	10	2	95	1	50	30
8	5	10	2	95	1	50	30

Serum and tissue sampling

Forty-eight hours after the last training session, animals were anesthetized by intraperitoneal injection of ketamine )80 mg/kg( and xylazine )10 mg/kg( and blood samples were taken from the animal's heart, and hippocampal tissues were harvested. Blood samples were then placed at room temperature for 30 minutes and then centrifuged at 1000 × g for 20 minutes at 4°C, and serum samples were stored at a temperature of -80°C. The hippocampus was washed in PBS solution. An ultrasonic homogenizer performed homogenization in Ripa buffer solution with protease inhibitor on ice. The homogenate was centrifuged at 4°C at 13,000 rpm for 20 minutes, and the supernatant was kept at -80°C.

Western blot

Western blotting was used to measure the amount of AMPK, GSK3-β, AdipoR1, AdipoR2, and the phosphorylated form of Tau protein and insulin receptor beta subunit (IRB). The total protein concentration in the hippocampal samples was measured by the Lowry method, while bovine serum albumin was used as standard. After matching the concentrations, 40 µg of protein from each sample was mixed with a buffer sample. Then electrophoresed was performed for 75 minutes using 11% SDS-PAGE gel. After that, the proteins separated in the gel were transferred to PVDF paper. The membrane was then incubated in 2% block solution overnight (at 4°C). In the next step, the membrane was quenched four times each washed with TBST solution for 5 minutes and incubated for 3 hours with the initial antibody (concentration 1.200) for each of the mentioned proteins. Then, the membrane was exposed to a secondary antibody (with a concentration of 1.1000) for 1 hour. In the next step, immune detection was recorded using Chemi Doc XRS + imaging system (Bio-Rad Company, USA) and analyzed by ImageJ software [27]. β-actin was used as a control.

ELISA

The adiponectin concentrations and insulin were assessed using ELISA in the serum and hippocampus supernatant. According to the manufacturer's instructions, serum and tissue adiponectin and insulin were assayed using relevant kits. Adiponectin (Rat ELISA Kit, Eastbiopharm) and insulin (Rat ELISA Kit, Eastbiopharm) [27, 28].

Calculation of insulin resistance/sensitivity indices

The homeostasis model assessment (HOMA) was used to assess insulin resistance (HOMA-IR) and pancreatic β-cell function (HOMA-β). Specifically, HOMA-IR and HOMA-β scores were calculated using the following formula: HOMA-IR= [(fasting glucose (mmol/L) × fasting insulin (µU/mL))/22.5]. HOMA β-cell= [(20 × fasting insulin (µU/mL)) / (fasting glucose (mmol/L) – 3.5) [29]. The quantitative insulin sensitivity check index (QUICKI) was also used as it has a better linear correlation with glucose clamp determinations of insulin sensitivity than minimal-model estimates. QUICKI was calculated using Katz et al. formula [30] (i.e., 1/[log (fasting insulin in µU/ml) + log (fasting glucose in mg/dl)]).

Statistical analysis

The data are reported as mean ± standard deviation (SD). Statistical analysis was performed using SPSS version 21. Normality and homogeneity of variances were assessed using Shapiro-Wilk and Leven tests, respectively. One-way ANOVA followed by Tukey's post-hoc was used to analyze the data. P values less than 0.05 were considered statistically significance.

Animal weight and blood glucose

We assessed the effect of our diabetes induction accuracy and exercise protocol efficiency. Our results showed that blood glucose was significantly increased one week after STZ injection compared with before STZ injection in T2D and T2D + Ex group (P = 0.000), with no significant difference between these groups. In addition, HIIT reduced blood glucose significantly (P = 0.000) (Fig. 1).

Animals’ weight showed a significant increase in T2D and T2D + Ex groups after two months of high-fat diet and before STZ injection (P = 0.000). In addition, the weight was decreased in T2D and T2D + Ex groups (P = 0.000) with more decrease in the T2D group (P = 0.02) (Fig. 2).

Insulin resistance/sensitivity indexes

Our result showed that T2D had higher HOMA-IR than Con and Ex groups (P < 0.05), but there is no significant difference between Ex and Con groups. In addition, a significant difference was shown between T2D and T2D + Ex groups (P = 0.04) (Fig. 3-A). HOMAβ showed a significant difference between the groups with Ex and T2D as the highest and lowest, respectively (P ≤ 0.05). In addition, HOMAβ was higher in T2D + Ex than the T2D group (P < 0.05) (Fig. 3-B). QUICKI was different between all groups, with T2D and Ex being the highest and lowest, respectively (P < 0.05). Furthermore, QUICKI was higher in T2D + Ex than the T2D group (P < 0.05) (Fig. 3-C).

Insulin levels in serum and hippocampus

Our results showed that serum insulin levels were significantly different in Con from T2D group (P < 0.05). In addition, T2D + Ex group showed significantly higher levels of serum insulin levels than the T2D group (P < 0.05). Hippocampus insulin levels were significantly different in Con from other groups (P < 0.05). Furthermore, Ex and T2D + Ex groups showed higher hippocampal insulin levels than the T2D group, with Ex as the highest (P < 0.05) (Fig. 4).

Adiponectin levels in serum and hippocampus

Our results showed that adiponectin levels in serum and hippocampus were significantly different in Con from other groups (P < 0.05). So that exercise and diabetes increase and decrease, adiponectin levels in serum and hippocampus, respectively. In addition, T2D + EX group showed higher adiponectin levels in both serum and hippocampus than the T2D group (P < 0.05) (Fig. 5).

InsRB levels in hippocampus

InsRB levels were significantly difference between groups with the highest and lowest in Ex and T2D groups, respectively (P < 0.05). Furthermore, InsRB levels were significantly higher in T2D + Ex as compared with the T2D group (P < 0.05) (Fig. 6).

APNR1 and APNR2 levels in the hippocampus

APNR1 and APNR2 levels showed a significant difference between groups with the highest and lowest in Ex and T2D groups, respectively (P < 0.05). Furthermore, APNR1 and APNR2 levels were significantly higher in T2D + Ex compared with the T2D group (P < 0.05) (Fig. 7).

AMPK levels in the hippocampus

AMPK levels in the hippocampus showed a significant difference between groups with the highest and lowest in Ex and T2D groups, respectively (P < 0.05). Furthermore, AMPK levels were significantly higher in T2D + Ex compared with the T2D group (P < 0.05) (Fig. 8).

GSK3β levels in the hippocampus

GSK3β levels in the hippocampus were significantly different between groups with the highest and lowest in Ex and T2D groups, respectively (P < 0.05). Furthermore, GSK3β levels were significantly higher in T2D + Ex compared with the T2D group (P < 0.05) (Fig. 9).

TAU levels in the hippocampus

TAU levels in the hippocampus showed a significant difference between groups with the highest and lowest in Ex and T2D groups, respectively (P < 0.05). Furthermore, TAU levels were significantly higher in T2D + Ex compared with the T2D group (P < 0.05) (Fig. 10).

This study was designed to investigate the effect of eight-week HIIT on adiponectin signaling and AD risk factors in the hippocampus of male rats with T2D. Our results showed that diabetes reduced both insulin and adiponectin levels in serum and hippocampus. Diabetes also reduced the expression of adiponectin and insulin receptors and AMPK and increased dephosphorylated GSK3-β and Tau in the hippocampus. HIIT recovered these impairments fully or partially. HOMA-IR, HOMA-β, and QUICKI (i.e. indices of insulin resistance, β cells function, and insulin sensitivity, respectively) were also improved by HIIT. In line with our results, Ghiasi et al. [31] reported that while HOMA-IR increases and QUICKI and HOMA-β are decrease in diabetes, HIIT returned these indices to the normal ranges.

It has been suggested that diabetes-induced peripheral IR could finally lead to central IR. This can explain the decrease in hippocampal insulin and insulin receptor expression in the T2D group, consistent with Biessels et al. results [32].

One study suggested that hypoadiponectinemia is associated with a decrease in hippocampus volume in patients with T2D [34] and adiponectin levels are critical for brain function. Pousti et al. [33] revealed that adiponectin modulates synaptic plasticity in the hippocampal dentate gyrus. Furthermore, Weisz et al. [34] demonstrated that adiponectin signaling could regulate hippocampal synaptic transmission. The recovery of adiponectin level and its receptors in hippocampus of diabetic rats through exercise, reported in the present study, shows that HIIT may be used as a non-pharmacological strategy for prevention and treatment of hippocampus function impairments induced by diabetes/AD. At the behavioral level, diabetes can adversely affect cognitive-related function such as the results of Morris water maze [35] and adiponectin improved animal performance in this test [36, 37]. Our results also showed a negative effect of diabetes on adiponectin levels and its receptors in the hippocampus, which are in agreement with other studies [38, 39].

In line with our results, many studies have shown that exercise can improve HOMA indices and IR [40, 41]. In addition, it has been suggested that HIIT can improve insulin sensitivity and increase insulin secretion [42]. Our observations also confirmed the positive effects of HIIT on insulin sensitivity and insulin secretion. Hemmatinafar et al. [43] reported that HIIT is a time-efficient method for increasing adiponectin levels and reducing body fat considering the point that exercise intensity is the vital variable in affecting adiponectin. It means that the more exercise intensity the more increase in adiponectin. Added to this, the interval nature of HIIT allows to repeat several bouts of high intensity exercises, reinforcing the HIIT associate advantages [44].

In addition, we saw increased Tau levels in the hippocampus in T2D which is in line with Hobday et al. [45] results. AMPK/GSK-3β pathway dysfunction is considered as the main reason for increased Tau accumulation because of increased GSK-3β activity which finally leads to its hyper-phosphorylation [46]. Adiponectin could also stimulates AMPK in the hypothalamus and increases food intake [47]. This may justify the weight loss we saw in diabetic animals.

Our results also showed that the hippocampus level of adiponectin, adiponectin receptors and AMPK are reduced in diabetic rats but HIIT seems to recover these changes. In peripheral tissue, adiponectin activates AMPK through AdipoR1. Furthermore, AMPK promotes Akt phosphorylation and GSK-3β inhibition, both of which increase insulin sensitivity. Activating this signaling pathway also suppresses apoptosis, oxidative stress, and neuro inflammation and it could reduce neurodegeneration. It has been shown that adiponectin could improve memory and synaptic plasticity in a rat model of dementia, and AMPK is essential for the memory-improving effect of adiponectin [48]. Barone et al. [49] showed that the interplay between oxidative stress, brain IR and AMPK dysfunction contribute to neurodegeneration in T2D and AD. They reported a decrease in AMPK in the hippocampus of diabetic patients and consider decrease adiponectin, increase oxidative stress and inflammation, and increase GSK3B activity as the main players in this scenario [49]. Many studies [50, 51] have shown that HIIT can increase AMPK levels and expression in the skeletal muscle. Exercise has long been known to activate AMPK/Sirtuin1 (AMPK/SIRT1) pathway and enhance brain-derived neurotrophic factor (BDNF) production. The activation of AMPK/SIRT1 and BDNF play an important role in exercise-related mitigation of dementia pathology. AMPK/SIRT1 and BDNF can directly affect intracellular Aβ production, Tau phosphorylation, and neurogenesis via regulating α-, β-,γ-secretases, and GSK3 [52]. Activated GSK-3, phosphorylates and thereby inactivates glycogen synthase, an enzyme that converts glucose to glycogen for storage [53] (Fig. 11).

Insulin activates AKT/protein kinase B through a well-defined mechanism mediated by the IRS1/PI3K pathway. This leads to the phosphorylation of GSK3B at serin9 residual, resulting in its inactivation [54]. Our results showed increased expression of GSK3B in the hippocampus following T2D. Adiponectin can modulates the GSK3B signaling pathway [53] and evidence supports GSK3's role in producing some of AD's characteristic hallmarks, such as extracellular accumulation of amyloid-β protein (Aβ) and intra neuronal neurofibrillary tangles composed of hyper-phosphorylated tau and inflammatory markers. These effects contribute to synaptic and neuronal loss and memory decline [55]. GSK3β was recognized as a primary kinase involved in tau phosphorylation, as was apparent from the first study termed tau protein kinase-I. Thus, GSK3β has been identified as one of the major enzymes mediating Tau hyper-phosphorylation at the residues implicated in neurodegenerative Tauopathies, including AD [56]. Our results, showed its increased expression in the hippocampus following T2D. Thota et al. [57] results are consistent with our data. The recovery of adiponectin levels and reduction of GSK3B expression towards normal by HIIT in diabetic rats, imply that this type of exercise would benefit patients with diabetes to prevent the progression of their memory loss during the course of disease.

Our results confirmed the destructive effects of T2D on the levels of specific Alzheimer's-related markers in the hippocampus through adiponectin signaling. T2D decreased insulin and adiponectin levels in serum and hippocampus as well as the hippocampal levels of insulin and adiponectin receptors and AMKP but increased GSK3β and Tau in the hippocampus and HIIT as a non-pharmacological intervention, could recover these impartments.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by Ethics committee of KUMS (Ethics Approval Code: IR.KMU.REC.1399.503).

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

All data and material is available at https://kmu.ac.ir/en by request.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Funding

This study was funded by Physiology Research Center and Neuroscience Research Center of Kerman University of Medical Sciences (grants No. 99000443, and 99-42).

Authors' contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Kayvan Khoramipour, Mohammad Abbas Bejeshk, and Mohammad Amin Rajizadeh. The first draft of the manuscript was written by Kayvan Khoramipour, Mohammad Abbas Bejeshk, and Mohammad Amin Rajizadeh. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript

Acknowledgements

We would like to thanks Physiology Research Center and Neuroscience Research Center of Kerman University of Medical sciences for their financial help.

Compliance with Ethical Standards

Disclosure of potential conflicts of interest

The authors have no relevant financial or non-financial interests to disclose.

Research involving Human Participants and/or Animals

Yes

Informed consent

Not applicable.

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published 06 Mar, 2023

Read the published version in Molecular Neurobiology →

Reviewers agreed at journal
20 Jul, 2022
Reviewers invited by journal
19 Jul, 2022
Editor invited by journal
28 Jun, 2022
Editor assigned by journal
20 Jun, 2022
First submitted to journal
07 Jun, 2022

You are reading this latest preprint version

High-intensity interval training ameliorate diabetes-induced disturbances in Alzheimer's-related factors in the hippocampus through adiponectin signaling

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Material And Methods

Animal care

Induction of diabetes

Exercise protocol

Serum and tissue sampling

Western blot

ELISA

Calculation of insulin resistance/sensitivity indices

Statistical analysis

Results

Animal weight and blood glucose

Insulin resistance/sensitivity indexes

Insulin levels in serum and hippocampus

Adiponectin levels in serum and hippocampus

InsRB levels in hippocampus

APNR1 and APNR2 levels in the hippocampus

AMPK levels in the hippocampus

GSK3β levels in the hippocampus

TAU levels in the hippocampus

Discussion

Conclusion

Declarations

References

Status:

Journal Publication

Version 1

week	Frequency	intervals	High-intensity interval duration (min)	Low-intensity interval duration (min)	High-intensity interval velocity (Vmax)	Low-intensity interval velocity (Vmax)	Total exercise time in a session (min)
1	5	4	2	80	1	50	12
2	5	4	2	80	1	50	12
3	5	6	2	85	1	50	18
4	5	6	2	85	1	50	21
5	5	8	2	90	1	50	24
6	5	8	2	90	1	50	24
7	5	10	2	95	1	50	30
8	5	10	2	95	1	50	30

week	Frequency	intervals	High-intensity interval duration (min)	Low-intensity interval duration (min)	High-intensity interval velocity (Vmax)	Low-intensity interval velocity (Vmax)	Total exercise time in a session (min)
1	5	4	2	80	1	50	12
2	5	4	2	80	1	50	12
3	5	6	2	85	1	50	18
4	5	6	2	85	1	50	21
5	5	8	2	90	1	50	24
6	5	8	2	90	1	50	24
7	5	10	2	95	1	50	30
8	5	10	2	95	1	50	30

week	Frequency	intervals	High-intensity interval duration (min)	Low-intensity interval duration (min)	High-intensity interval velocity (Vmax)	Low-intensity interval velocity (Vmax)	Total exercise time in a session (min)
1	5	4	2	80	1	50	12
2	5	4	2	80	1	50	12
3	5	6	2	85	1	50	18
4	5	6	2	85	1	50	21
5	5	8	2	90	1	50	24
6	5	8	2	90	1	50	24
7	5	10	2	95	1	50	30
8	5	10	2	95	1	50	30