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| ORIGINAL ARTICLE |
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| Year : 2019 | Volume
: 62
| Issue : 6 | Page : 261-266 |
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Sex Differences in antiaging response to short- and long-term high-intensity interval exercise in rat cardiac muscle: Telomerase activity, total antioxidant/oxidant status
Marziyeh Saghebjoo1, Saber Sadeghi-Tabas1, Iman Saffari1, Azin Ghane2, Ivan Dimauro3
1 Department of Exercise Physiology, Faculty of Sport Sciences, University of Birjand, Birjand, Iran
2 Department of Exercise Physiology, Islamic Azad University, Science and Research Branch, Tehran, Iran
3 Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, Rome, Italy
| Date of Submission | 27-Jul-2019 |
| Date of Acceptance | 05-Nov-2019 |
| Date of Web Publication | 29-Nov-2019 |
Correspondence Address:
Dr. Marziyeh Saghebjoo
Department of Exercise Physiology, Faculty of Sport Sciences, University of Birjand, Birjand
Iran
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/CJP.CJP_52_19
Cardiovascular disease prevails with age which varies according to sex. Telomere length plays an important role in aging. Despite the great benefits of high-intensity interval training (HIIT), the acute responses to HIIT with different intervals have not been elucidated in different sexes. This study was conducted to investigate the sex-dependent responses of telomerase enzyme activity, total oxidant status (TOS), total antioxidant capacity (TAC), and the ratio of TAC/TOS to short- and long-term high-intensity interval exercise (HIIE) in cardiac muscle of male and female rats. Forty adult Wistar rats were randomly allocated to six groups: male and female HIIE with short-term intervals (MHIIESh and FHIIESh, respectively), male and female HIIE with long-term intervals (MHIIEL and FHIIEL, respectively), and controls groups. Telomerase activity, TAC, and TOS levels were examined immediately after exercise in the cardiac muscle. The level of telomerase enzyme activity, TOS level, and the ratio of TAC/TOS did not change after HIIE with short-term interval and HIIE with long-term interval (HIIEL) in male and female rats (P = 0.52, 0.69, and 0.08, respectively). There was a statistically significant decrease in the TAC level in the MHIIESh group (P = 0.04). Furthermore, a significant decrease was observed in the HIIEL in both male and female rats (P = 0.03 and 0.04, respectively). Acute exposure to HIIE with short- and long-term intervals would not result in a significant change in some indicators of biological aging. However, due to gender-specific biological differences, further studies will provide evidence regarding the roles of HIIE at different times of intervals, which contribute to aging prevention.
Keywords: Cardiac muscle, high-intensity interval exercise, sex differences, telomerase activity, total antioxidant/oxidant status
How to cite this article:
Saghebjoo M, Sadeghi-Tabas S, Saffari I, Ghane A, Dimauro I. Sex Differences in antiaging response to short- and long-term high-intensity interval exercise in rat cardiac muscle: Telomerase activity, total antioxidant/oxidant status. Chin J Physiol 2019;62:261-6 |
How to cite this URL:
Saghebjoo M, Sadeghi-Tabas S, Saffari I, Ghane A, Dimauro I. Sex Differences in antiaging response to short- and long-term high-intensity interval exercise in rat cardiac muscle: Telomerase activity, total antioxidant/oxidant status. Chin J Physiol [serial online] 2019 [cited 2021 Mar 7];62:261-6. Available from: https://www.cjphysiology.org/text.asp?2019/62/6/261/272026 |
| Introduction | |  |
The prevalence, incidence, and morbidity of cardiovascular disease (CVD) increased with the aging human population. Several factors, including biological age, sex hormones, and sex chromosomes, influence cardiovascular phenotype during the lifespan.[1] Regular participation in physical activity has demonstrated to decrease cardiovascular events.[2],[3] In particular, physical training improves endothelial function, blood pressure, insulin sensitivity, body weight, as well as oxidative and inflammatory parameters.[4]
On cellular level, a key aging process is the shortening of telomeres to a critical telomere length where cells enter replicative senescence or programmed cell death.[5] Telomeres are the protective cap at the end of chromosomes, which shrink by each cellular replication.[6] The length of the telomere is similar at birth in both sexes but shortens more rapidly throughout life in men than that of women.[1] Telomere attrition occurs in most cell/tissue types with age and is associated with many age-related phenotypes and diseases such as CVD and most cancers.[7] Telomere length is regulated by the reverse transcriptase telomerase that prevents successive shortening of telomeres.[8] The importance of telomerase has been highlighted in those cell models where a deficiency of this enzyme accelerated aging and rates of telomere attrition.[9]
The cellular environment plays an important role in telomere length regulation and telomerase activity. Indeed, it is known that oxidative stress can accelerate telomeres' shortening, whereas antioxidants can decelerate telomere shortening.[10],[11] Telomeres are sensitive to oxidative stress with women producing less reactive oxygen species (ROS) than men. It has been suggested that women might also metabolize ROS better because of estrogen thanks to its antioxidant properties.[12] Although there is still much debate about the beneficial effects of physical activity on preserving age-related telomere attrition,[13],[14],[15] to date, it is not clear how acute exercise can modify telomere biology. Some authors have suggested that physical activity can increase the concentration and activity of telomerase, proposing this enzyme as one of the key molecules in telomere homeostasis.[16] On the other hand, the relationship between the types of acute exercise remains unclear. For example, Denham et al. reported that acute periods of moderate exercise could lead to a decrease in telomere activity.[17] It has also been demonstrated that acute exposure of endurance trail race reduced telomere length and telomere activity.[18] Although most studies have performed in human participants and blood samples,[19] therefore, the relationship between the two types of high-intensity interval exercise (HIIE) and sexes in rat cardiac muscle has not been well described.
In addition, severe exercise leads to an increase in total oxidant status (TOS) and extreme yield of free radicals that can cause by oxidative stress.[20] On the other hand, oxidative stress is naturally occurring by the activation of eternal antioxidant protection. All organisms have progressed an antioxidant protection system to counter ROS yields. This system is defined by total antioxidant capacity (TAC), which significantly delays or prevents oxidation. Indeed, misbalance between TOS and TAC is associated with many pathological diseases such as CVD. Furthermore, aging is involved in a gradual reduction of TAC and increased TOS.[21],[22] Furthermore, relations between TAC and TOS with exercise training are affected by the period of exercise, intensity, and mode.[23] As some direct relations in the intensity of exercise and changes in TAC and TOS have been reported in studies,[20],[24] the TAC and TOC analysis was included in our consideration. For instance, Bloomer et al. revealed that HIIE decreased ROS production and improved antioxidant defense system,[25] whereas Goto et al. highlighted that HIIE could increase oxidative stress.[26] However, the effect of short- and long-term HIIE in total oxidant/antioxidant status in cardiac muscle has not yet to be elucidated.
Also, in this study, we utilized short- and long-term of HIIE to analyze the sex differences in response of parameters related to oxidative and telomere homeostasis to these HIIEs. In particular, we aimed to investigate if two types of HIIE with the same volume and intensity (with different patterns of activity and recovery time) can modulate the telomerase enzyme activity, TAC and TOS levels, and the ratio of TAC/TOS in the cardiac muscle of male and female Wistar rats. An analysis of the changes induced by acute exercise on these parameters will help us to understand not only the effectiveness of the proposed exercise in the short term but also its potential beneficial effects when given for a long period.
| Subjects and Methods | | |
Study design and animals
Forty Wistar rats (20 male and 20 female rats, aged 8 weeks, mean weighting 270 g and 225 g, respectively) were obtained from the experimental medical research center (Birjand University of Medical Sciences) and were housed in Animal Sciences Laboratory at the University of Birjand in an environmentally controlled room (temperature 25°C ± 2°C and relative humidity 50% ± 2%) with a 12 h cycles of light/dark, water, and food ad libitum. After a week of acclimatizing with a new environment, rats were randomly divided into six groups: male control (n = 6), female control (n = 6), male HIIE with short-term intervals (HIIESh) (n = 7), female HIIESh (n = 7), male HIIE with long-term intervals (HIIEL) (n = 7), and female HIIEL (n = 7). All experiments were approved by the Ethics Committee of the Birjand University of Medical Sciences (IR.BUMS.REC.1396.54).
Exercise intervention
The exercise program includes three steps:
- Warm up for 5 min on the treadmill with 40% of maximum oxygen uptake (15 m/min).[27]
- The main exercise involving: (i) HIIESh: the exercise program was included 16 two-min intervals that was performed for 32 min (regardless of warming-up and cooling-down time), including 1 min with an intensity of 80%–95% VO2max, equivalent to a speed of 40 m/min and 1 min with an intensity of 50%–60% VO2max, equivalent to a speed of 16 m/min[28] [Figure 1]a or (ii) HIIEL: the exercise program was included 4 eight-min intervals that was performed for 32 min (regardless of warming-up and cooling-down time), including 4 min with an intensity of 80%–95% VO2max, equivalent to a speed of 40 m/min and 4 min with an intensity of 50%–60% VO2max, equivalent to a speed of 16 m/min [Figure 1]b.[27],[28]
- Cool down for 5 min on the treadmill with 40% of maximum oxygen uptake (15 m/min).[27]
 | Figure 1: High-intensity interval exercise protocols. HIIESh: High-intensity interval exercise with short-term intervals (a), HIIEL: High-intensity interval exercise with long-term intervals (b).
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Sampling and tissue homogenization
The rats were euthanized (intraperitoneal injection, ketamine and xylazine 100 mg/10 mg/kg, respectively) just after completing the exercise protocol. Heart of rats was removed, and after washing with normal saline, the heart samples were frozen with immersing into liquid nitrogen (−196°C) and then stored at −80°C until the next assays.
Weighting and incision of the heart tissue were followed by homogenate in phosphate-buffered saline (pH 7.4, 100 mM, 100 mg tissue/1 ml PBS) using a homogenizer. Protein degradation was prevented by a protease inhibitors cocktail (ProBlock, Goldbio Inc., USA) addition to the lysis buffer. Centrifugation (6000 rpm, 4°C, 10 min) was used for supernatants collection. The aliquot was prepared and stored at −80°C for the following determinations.
Measurement of telomerase activity
For this purpose, a telomerase activity assay kit (Telo TAGGG PCR, ELISA kit, Boehringer Mannheim, Mannheim, Germany) based on the polymerase chain reaction and ELISA method were used for the measurement of telomerase enzyme activity. The procedure done by the kit insert follows upping. Centrifugation (16,000 g, 4°C and 20 min) was used for tissue homogenate clearing which is used for telomerase activity and also sensitive Bradford protein content determination (Bradford total protein assay kit, ZellBio GmbH, Ulm, Germany).
Briefly, telomerase in the tissue sample added the telomeric repeats (TTAGGG) to the 3′ end of a synthetic primer with biotin labeled. A denaturation solution (20 μl) was added, then 5 μl of the amplification product added, after an initial elongation/amplification reaction. Finally, hybridization buffer put into the reaction. After the addition of anti-digoxigenin peroxidase antibody (100 μl, 2 h) to the microplate wells, 100 μl TMB substrate (3, 3′5, 5′-tetramethyl Benzidine) was added. Finally, a blocking reagent stopped the peroxidase reaction, and the optical absorbance (OD) at 450 nm and 620 nm were recorded. The obtained result was expressed as a ratio of the sample to control OD. The calculated mean OD of the control group was considered as 100%.
Measurement of total antioxidant capacity and total oxidant status levels
Tissue TAC and TOS levels were measured by relevant chemical colorimetric assay kits (TAC and TOS assay kits) manufactured by ZellBio GmbH, Ulm, Germany. Sensitivity of the TAC and TOS assays was 0.1 mM and 0.5 μM, respectively. The TAC and TOS intraassay precision was 4.6% and 5.1%, respectively.
Statistical analysis
After examining the normality of data distribution using the Shapiro–Wilk test, two-way ANOVA and Tukey post hoc test were used to determine the difference between the groups. Analyses were performed using the SPSS software version. 20. Statistical significance was set at P < 0.05. GraphPad Prism version 6 (Graph Pad Software Inc., La Jolla, CA, USA) software was also used to plot the graphs.
| Results | | |
Telomerase activity
The results did not show a significant difference in telomerase enzyme activity in the heart muscle of male and female rats in response to HIIEs with short- and long- term intervals (P = 0.52). However, telomerase enzyme activity in female rats showed a tendency to increase by 9% after HIIESh and 11.5% following HIIEL compared to the control group [Figure 2]a. | Figure 2: Telomerase activity in cardiac muscle after high-intensity interval exercise with short-and long-term intervals (a). Total antioxidant capacity in cardiac muscle after high-intensity interval exercise with short- and long-term intervals (b). Total oxidant status in cardiac muscle after high-intensity interval exercise with short- and long-term intervals (c). The ratio of total antioxidant capacity/total oxidant status after high-intensity interval exercise with short- and long-term intervals (d). Ctr, male and female control groups; HIIESh, male and female high-intensity interval exercise with short-term intervals groups; HIIEL, male and female high-intensity interval exercise with long-term intervals groups; data are presented as mean ± standard deviation *Statistical significance at P < 0.05.
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Total antioxidant capacity level
There was a significant difference between male and female rats in response to two different HIIEs (P = 0.005). The TAC level decreased in response to HIIESh in male rats (P = 0.04). Furthermore, a significant decrease was observed in response to HIIELs in male and female rats (P = 0.03 and 0.04, respectively), [Figure 2]b.
Total oxidant status level
The level of TOS did not change in male and female rats in response to HIIEs with short- and long-term intervals groups (P = 0.69). However, the TOS level showed a tendency to decrease in female rats by 37.5% in the HIIESh group and 35.6% in the HIIEL group compared to the control group [Figure 2]c.
The ratio of total antioxidant capacity/total oxidant status
The ratio of TAC to TOS did not change in response to HIIEs with short- and long-term intervals in both male and female rats (P = 0.08), [Figure 2]d.
| Discussion | | |
The results of the current study indicated that telomerase enzyme activity did not change in the heart muscle in male and female rats following HIIEs with short- and long-term intervals. However, it increased by 9% following HIIE with short term and 11.5% after HIIE with long term in the female rats. Furthermore, the TAC level decreased following HIIELs in male and female rats. Likewise, the TAC level decreased in male rats after HIIEShs. On the other hand, the level of TOS did not show a significant difference in male and female rats after HIIEs with short- and long-term intervals. However, TOS level decreased by 37.5% and 35.6% in the female after HIIEs with short- and long-term intervals, respectively. Furthermore, the TAC to TOS ratio did not show a significant difference in male and female rats after HIIEs with short- and long-term intervals.
Telomeres are including repeated DNA suit and the polyprotein multiplex shelterin. Due to the end transcription problem and some other degradative functions in telomerase, in every cell division, it gets shorter.[29] In fact, the shortening of telomere can be converted by the action of telomerase which is a major enzyme complex required for maintaining telomeric length. The studies have shown that maintain lengthening of telomeres enhances many health factors.[19],[30] For instance, Rehkopf et al. reported that telomere length relatively involved in known as cardiovascular risk markers, and it has been introduced as a major factor of CVDs.[30]
Furthermore, telomerase activity might be a more direct and potentially predictor than telomere length which is involved in long-term cellular viability, genomic stability, and the process of diseases.[31],[32] Telomerase enzyme activity plays an important role in cardiac development. In addition, it is necessary for cardiomyocyte multiplication which can delay cell-cycle exit in cardiomyocytes. Indeed, if on the one hand, a forced telomerase expression proved to lengthen cardiac myocyte cycling and hypertrophy.[30] On the other hand, the lack of telomerase has shown to accelerate aging in a cell model.[15],[33] In this respect, it has been shown that telomere shortening and reduction of telomerase activity are one of the cellular factors of aging.[34] Since telomerase activity can be regulated at multiple approaches, exercise training is a potential approach that has effects on cellular aging and changes telomerase activity.[35]
It has been shown that telomerase activity has significantly increased, following short-term (3 weeks) and long-term (6 months) exercise training in rodent heart tissue.[36],[37] The result of the present study did not show a significant change in telomerase activity levels after acute HIIEs with short- and long-term intervals. Indeed, one bout of HIIE may not has been effect on telomerase because the levels of this enzyme need to adapt with several bouts of HIIE. Ludlow et al. showed that 30 min of treadmill running with approximately 70% of peak speed caused slight rise of telomerase activity in the cardiac muscle of female mice, but it was not significant.[38] Regarding the effects of acute exercise in telomerase activity in human studies, Zietzer et al. showed 30 min treadmill running increased the telomerase activity.[39] Also, in another study, Chilton et al. indicated that acute exercise enhanced the telomerase activity in young men.[16] Since telomerase activity may have multiple doses range below and above, telomeric and nontelomeric effects may happen at different levels of this enzyme.[40] However, a direct comparison cannot be made because these studies have been done in the human model. Further studies are needed to compare these protocols in animal models. It is important to point out that no significant changes were observed in telomerase activity, it may be related to the frequency of exercise because the activity of this enzyme should be adapted to exercise stress.[41]
Oxidative stress could cause to increase free radicals and/or decrease antioxidant capacity. Oxidative stress has a crucial role in contributor to senescence-related CVD. The cardiomyocytes are more relevant to oxidative stress which is causing damage in the structural and functional of the heart.[42] Furthermore, oxidative stress-mediated cellular detriment through ROS involved in the senescence process.[43] Acute exercise can cause oxidative stress in animals and humans.[44] It has been proved that oxidative stress can accelerate the telomere shortening and inhibit telomerase activityin vitro in various cell types.[18] On the other hand, sex hormones are associated with the production and management of ROS. For instance, estrogen could decrease the production of ROS, and it is a potential factor to regulate antioxidant genes. Conversely, testosterone has not antioxidant properties, and it is linked to increased susceptibility to oxidative stress.[15] In the present study, the level of TAC in response to HIIESh has significantly decreased in male rats. Also, in the HIIEL groups, a significant decrease was observed in both male and female rats. These results suggest that different sex responses to the antioxidant capacity following acute exercise could indicate higher antioxidant capacity of female rats than males.[45] In this context, Yamamoto et al. indicated that antioxidant capacity in female rats significantly increased that it might associate with glutathione levels. Exercise training could alter antioxidant capacity, seem to be affected by sex differences.[46] However, the level of TOS did not have a significant difference in response to acute HIIEs with short- and long-term intervals. Although, the results showed that, the level of TOS decreased by 37.5% following HIIEs and 35.6% after short- and long-term intervals in female groups. Balcı and Pepe reported that exercise training decreased malondialdehyde levels (as an oxidative stress factor) in the heart and gastrocnemius tissues in female rats.[47] Regarding these results, and given the different role of TOS in cardiac aging factors, it is important that further studies focus on the potential role of TOS to act against chronic heart disease. Taken these data together, the results of the current study revealed a reduction in antioxidant capacity following one bout of HIIE. However, telomerase activity and TOS did not change in heart tissue. Thus, this type of acute exercise does not seem to change telomere length, although several bouts of HIIE may increase the telomerase activity female rats. According to the antiaging effects of HIIE in heart muscle, more studies necessary to indicate chronic effects (several bouts) of HIIE on cardiac aging factors.
| Conclusion | | |
In summary, despite the reduction of antioxidant capacity following acute exposure to HIIE with short- and long-term intervals, it will not result in a significant change in some indicators of biological aging. However, due to the biological differences between sexes, further studies are needed to provide evidence for important roles of HIIE with different time intervals to support aging prevention.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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