The effect of resistance training and testosterone consumption on Caspse3 gene expression in the heart tissue of male Wistar rats
Subject Areas : Sport Physiology
Reyhane Ghanei
1
,
َAbdolali Banaeifar
2
,
Sajad Arshadi
3
,
Ali Gorzi
4
1 -
2 -
3 -
4 -
Keywords:
Abstract :
Background: Studies show that cardiac tissue is one of the tissues that may be damaged as a result of anabolic steroid abuse. The aim of the present study was to study the effect of eight weeks of resistance training and testosterone consumption on the expression of caspase 3 under resistance training in the heart tissue of male Wistar rats.
Materials and Methods: In this study, 21 male Wistar rats (8 weeks old) with a mean weight of 252.20 ± 11.70 g were selected and divided into 3 groups: control, resistance training, and resistance training + testosterone. The resistance training protocol was performed five days a week (four sets of six with a rest of 60 to 90 seconds) in the form of climbing a 1-meter ladder, in which the weights were increased to 60% of the body weight in the first week and 20% of the rats' body weight each week. Testosterone enanthate injection was performed intramuscularly at a dose of 20 mg/kg, 3 days a week. To analyze the research findings, one-way analysis of variance test and Tukey's post hoc test were used to show the difference between groups (p≥0.05).
Results:
The results showed that the expression of caspase 3 in the exercise + testosterone group increased significantly compared to the control group (P=0.001). However, these changes in the exercise group did not show a significant difference compared to the control group (P≥0.05). Also, no significant change was observed between the two exercise and exercise + testosterone groups (P≥0.05).
Conclusion: Based on the results of the present study, it can be said that the use of supraphysiological doses of testosterone enanthate along with resistance training can increase apoptotic factors in the heart tissue of rats consuming enanthate and increase the possibility of myocardial damage.
Reihaneh Ghanei1, Abdolali Banaifar*2, Ali Garzi3, Sajad Arshadi2 1.PHD student, Department of exercise physiology, South Tehran Branch, Islamic azad university, Tehran, Iran. 2.Associated Professor, Department of exercise physiology, South Tehran Branch, Islamic azad university, Tehran, Iran 3. Associated Professor, Department of Sport Sciences, Faculty of Humanities, University of Zanjan. Zanjan. Iran |
*Corresponding author: Abdolali Banaeifar Address: Associated Professor, Department of exercise physiology, STC, Islamic azad university, Tehran, Iran Email: A.banaeifar@aiu.ir
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Abstract Background: Studies show that cardiac tissue is one of the tissues that may be damaged as a result of anabolic steroid abuse. The aim of the present study was to study the effect of eight weeks of resistance training and testosterone consumption on the expression of caspase 3 under resistance training in the heart tissue of male Wistar rats. Materials and Methods: In this study, 21 male Wistar rats (8 weeks old) with a mean weight of 252.20 ± 11.70 g were selected and divided into 3 groups: control, resistance training, and resistance training + testosterone. The resistance training protocol was performed five days a week (four sets of six with a rest of 60 to 90 seconds) in the form of climbing a 1-meter ladder, in which the weights were increased to 60% of the body weight in the first week and 20% of the rats' body weight each week. Testosterone enanthate injection was performed intramuscularly at a dose of 20 mg/kg, 3 days a week. To analyze the research findings, one-way analysis of variance test and Tukey's post hoc test were used to show the difference between groups (p≥0.05). Results: The results showed that the expression of caspase 3 in the exercise + testosterone group increased significantly compared to the control group (P=0.001). However, these changes in the exercise group did not show a significant difference compared to the control group (P≥0.05). Also, no significant change was observed between the two exercise and exercise + testosterone groups (P≥0.05). Conclusion: Based on the results of the present study, it can be said that the use of supraphysiological doses of testosterone enanthate along with resistance training can increase apoptotic factors in the heart tissue of rats consuming enanthate and increase the possibility of myocardial damage.
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The effect of resistance training and testosterone consumption on Caspse3 gene expression in the heart tissue of male Wistar rats
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Revised: 8 March 2025 Accepted: 9 April 2025
Keywords: Resistance Training, Caspase 3, Heart tissue, Testosterone Enanthate, Rats
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Journal of Sports Physiology and Athletic Conditioning Talk |
Journal of Exercise&
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Research Article |
Introduction |
Journal of Exercise&
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Anabolic-androgenic steroids (AAS) are frequently used by athletes as anabolic drugs to enhance sports performance. AAS are compounds derived from testosterone, the primary male hormone, which has long been utilized in medical sciences for treating certain diseases and can be administered in various forms, including oral and injectable (1). The use of AAS to restore or improve impaired physiological functions should be prescribed in precise and controlled doses (2). However, abuse of AAS at high doses far exceeds clinically recommended levels, particularly in non-medical contexts such as body aesthetics and sports performance enhancement, posing a significant challenge (3). Today, nearly all professional and semi-professional athletes use AAS. The global lifetime prevalence of AAS use is estimated at 3.3%, with 6.4% for men and 1.6% for women. However, this varies widely across countries, reaching up to 25% in some cases (4). It has been reported that 87% of performance-enhancing drugs among men and women are testosterone enanthate and testosterone propionate (5). The adverse effects of AAS abuse are associated with a wide range of side effects on the cardiovascular system, liver, and other tissues (6). The harmful effects of AAS abuse on the heart have increasingly been documented in the literature. Abuse of testosterone leads to serious side effects, including myocardial hypertrophy, myocardial fibrosis, and activation of apoptosis. Apoptosis causes the loss of myocardial cells and ultimately reduces myocardial function (7). Abuse of anabolic-androgenic substances is linked to sudden cardiac death, myocardial infarction, ventricular remodeling, and cardiomyopathy. These events are related to the activation of apoptosis due to AAS abuse. Myocardial death without coronary artery disease or |
or atherosclerosis has also been attributed to apoptosis induced by AAS (8). Exposure to supraphysiological doses of steroids can lead to heart weakening and enlargement, causing pathological hypertrophy (9). Damage to heart muscle due to long-term AAS abuse may be irreversible. Irreversible heart failure was reported after six months of treatment in a 31-year-old man who had used AAS for 12 years and growth hormone for one year. The patient had ceased abuse one year before hospital admission. The use of multiple steroid compounds combined with intense exercise appears to exacerbate this condition (10). A study by Zag and colleagues (2011) showed that 20 hours of exposure to stanozolol induced apoptosis in ventricular myocytes of adult mice under laboratory conditions, accompanied by increased Caspase 3 levels (8). Additionally, a study citing several cases of bodybuilder deaths following myocardial infarction after long-term AAS exposure noted that intense training combined with AAS abuse could lead to apoptotic changes in myocytes and endothelial cells (11). Studies suggest that oxidative stress, apoptosis, and inflammation caused by AAS, regardless of dose or duration of exposure, play a significant role in tissue damage and can be considered an independent risk factor for cardiovascular issues (10). Apoptosis is a physiological mechanism that eliminates unwanted, damaged, or dangerous cells without harming surrounding tissues and is essential for tissue development and homeostasis (12). Apoptosis occurs through two pathways: the intrinsic pathway, mediated by mitochondria, and the extrinsic pathway, mediated by death receptors on the cell membrane (12). Additionally, AAS can induce apoptosis, leading to the transition from |
compensatory cardiac hypertrophy to heart failure. Lopez and colleagues demonstrated that testosterone increases apoptosis in vascular smooth muscle cells through the extrinsic apoptosis pathway via reactive oxygen species (7). Caspases, as key indicators in apoptosis, play a crucial role in regulating the process. Caspases are classified into initiator caspases (e.g., Caspase 8 and 9), which activate early in the process, and executioner caspases (e.g., Caspase 3 and 6), which are activated later by initiator caspases and trigger the caspase cascade (13). Caspase 3, as the most prominent executioner, performs various functions. Due to its position at the intersection of multiple apoptosis induction pathways, Caspase 3 has gained a special place in apoptosis detection assays. Activation of this important protease by initiator caspases initiates the cell death cascade. For example, this enzyme is responsible for the cleavage and eventual degradation of multiple compounds involved in DNA regulation and repair (12, 13). On the other hand, epidemiological studies indicate that physical activity reduces the risk of at least 13 different types of cancer and provides evidence of its role in decreasing disease recurrence in various tissues (14). However, intense physical activity has been reported to mediate several factors that may alter apoptosis in different tissues. Currently, evidence exists for exercise-induced apoptosis in lymphocytes and skeletal muscles. For instance, glucocorticoids, removal of growth factors, reactive oxygen species (ROS), increased intracellular calcium levels, and tumor necrosis factor (TNF) are some signals that can induce apoptosis (15). Numerous studies have explored the impact of physical activity and exercise training on apoptosis. Some researchers have noted that a single session of |
intense exercise can accelerate apoptosis for up to 48 hours (13). In contrast, moderate and consistent exercise is likely to reduce apoptosis in various tissues (16). While many studies have investigated the effects of exercise and steroids separately, research on the combined effects of training and AAS on apoptosis markers, particularly Caspase 3 in heart tissue, remains limited. Nevertheless, some studies have addressed these issues. For example, Kara and colleagues (2018) demonstrated that stanozolol consumption in Wistar rats caused oxidative stress and stanozolol-induced apoptosis (17). Additionally, a study examining the effects of exercise and anabolic-androgenic steroids on hemodynamic factors, glycogen content, angiogenesis, apoptosis, and heart muscle histology in Wistar rats showed that, compared to the control group, the steroid group exhibited significantly higher blood pressure, heart rate, sympathetic nerve activity, testosterone levels, and cardiac Caspase 3 activity (18). As mentioned, the use of anabolic compounds, especially among young people and athletes aiming to strengthen muscles and enhance performance, is increasingly prevalent. Testosterone enanthate, due to its long-lasting effect (maintaining elevated plasma testosterone levels for about a week with a single injection), is more commonly used (19). However, studies investigating the effect of testosterone enanthate on Caspase 3, the most critical caspase in the apoptosis process (20), in resistance-trained rats are limited. The present study aims to examine the effects of resistance training and testosterone consumption on the Caspase 3 index in the heart tissue of Wistar rats, potentially providing valuable insights in this area.
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2. Materials and Methods |
Their heart tissues were then excised, washed in physiological serum, immediately frozen in liquid nitrogen, and stored at -80°C for variable analysis. Ethical guidelines for working with laboratory animals were followed per the ethics committee’s protocol. Biochemical Analysis of Variables: Caspase 3 gene expression was measured using PCR, with GAPDH as the control gene. The quality and quantity of extracted RNA were assessed using a Nanodrop device. cDNA synthesis was performed using the Takara kit (TAKARA cat NO. 6130) according to the manufacturer’s instructions. For RNA extraction, 50 mg of frozen heart tissue was h The average Ct values for replicate samples were calculated, and the comparative Ct method was used to determine relative gene expression levels omogenized, and RNA was extracted using a kit solution per the manufacturer’s protocol, purified with DNase I to remove DNA contamination and RNA-degrading enzymes. Two micrograms of mRNA were used to synthesize the first DNA strand. Relative gene expression in the heart was measured using specific primers (Table 1). Primers were designed using Oligo 7 software and blasted on the NCBI website for specificity and accuracy. The 260/280 nm absorbance ratio for extracted samples ranged from 1.8 to 2. RNA quality was verified using 1% agarose gel electrophoresis. Quantitative analysis was conducted using a StepOnePlus real-time PCR system (Applied Biosystems, Foster City, CA, USA). The average Ct values for replicate samples were calculated, and the comparative Ct method was used to determine relative gene expression levels.
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Subjects This experimental study involved 21 eight-week-old male Wistar rats with an average weight of 220 ± 15 grams, purchased from the Pasteur Institute of Iran and transferred to the laboratory. The animals were housed in washable polycarbonate cages under standard conditions (45-55% humidity, 12:12 light-dark cycle, 23°C temperature) with free access to water and food. Environmental conditions were monitored using ventilation systems, thermometers, and hygrometers to ensure suitability. Exercise Protocol: One week after acclimatization to the laboratory environment, familiarization training for ladder climbing was conducted for resistance exercise in rodents. The rats were then divided into three groups: control (7 rats), exercise (7 rats), and exercise + testosterone (7 rats). The exercise and exercise + testosterone groups underwent eight weeks of resistance training, five sessions per week (21). This involved four sets of six repetitions with 60-90 seconds of rest, climbing a 1-meter ladder with 26 steps and weights attached to the tails. The weight started at 60% of body weight in the first week, increasing by 20% of body weight weekly. In the fifth week, training intensity was maintained at the fourth week’s level to prevent overtraining, and in the final three weeks, it continued at 180% of body weight. The exercise + testosterone group received 20 mg/kg testosterone enanthate (manufactured by Iran Hormone, Iran, serial number 0069) via intramuscular injection three days per week (22). Forty-eight hours after the last training session and testosterone dose, following a 12-hour fast, the rats were anesthetized with a combination of xylazine (3-5 mg/kg) and ketamine (30-50 mg/kg). |
3. Results |
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Data normality was assessed using the Shapiro-Wilk test. One-way ANOVA was used to determine significant differences between variables, with Tukey’s post-hoc test applied if significant. Statistical analyses were performed at a significance level of P ≥ 0.05 using SPSS version 26. |
The results indicated a significant increase in Caspase 3 expression in the exercise + testosterone group compared to the control group (P = 0.001), with exercise + testosterone significantly elevating this index. However, no significant difference was observed in the exercise group compared to the control group, though a non-significant increase was noted. No significant difference was found between the exercise and exercise + testosterone groups (P = 0.147) (Figure 1). |
Table 1: Primer Sequence Specifications for Each Gene (Caspase 3) |
Gene | Forward | Reverse |
Caspse3 | GGAGTGACTGGAAAGCCGAA | CTTCTGGCAAGCCATCTCCTCA |
Figure 1: Average Caspase 3 Expression in Study Groups
= Significant change compared to the control group at α = 0.05. Chart 1: Chart Title |
and activated Caspase 3 (27). Some studies highlight the protective role of exercise against apoptosis, while others argue that intense exercise may increase apoptotic factors or decrease anti-apoptotic proteins, depending on exercise intensity, duration, type, and the health or fitness status of the subjects (14, 15). Regarding the effect of exercise + testosterone on Caspase 3, although limited studies exist, some clinical and sports studies align with the present findings, including those by Hasan Asma (2013) and Papamitsou (2011) (18, 28). Hasan Asma and colleagues (2013) showed that exercise and AAS increased cardiac Caspase 3 activity, with histological evidence of pathological cardiomyocyte hypertrophy and mild angiogenesis, suggesting potential cardiac damage from AAS use with exercise (18). Papamitsou (2011) reported that testosterone abuse in Wistar rats caused myocardial hypertrophy, fibrosis, and apoptosis (increased Caspase 3), with nandrolone potentially damaging DNA via ROS. Another experimental study on rabbits treated with 8 mg/kg nandrolone daily for 60 days confirmed increased Caspase 3 activity, supporting the toxic potential of AAS on cardiac tissue (28). Steroids may also increase pro-fibrotic cytokines like TGF-β in kidney tissue, promoting apoptosis and focal segmental glomerulosclerosis. Environmental and inflammatory stress can cause proteotoxic damage and regulate heat shock proteins. Studies suggest that oxidative stress and free radicals from AAS abuse enhance Caspase 3 activity, potentially altering mitochondrial respiratory chain complexes and monooxygenase systems, leading to an imbalance in free radical production (29-37). AAS exert a pre-apoptotic effect on cardiac myocytes, increasing sarcoplasmic reticulum Ca²⁺ release and mitochondrial permeability, |
Discussion |
The results of the present study regarding the Caspase 3 index show that resistance training led to a non-significant increase in Caspase 3 expression compared to the control group, while exercise + testosterone resulted in a significant increase. Consistent with this study, Hu and colleagues (2012) demonstrated that 12 weeks of intense aerobic training on a treadmill increased the expression of Caspase 3 and cytochrome C genes related to mitochondrial apoptosis in the cardiac muscle of Wistar rats, potentially exacerbating apoptosis via the intrinsic pathway (23). Similarly, Sharifi and colleagues (2017) found that resistance training at 80% 1RM increased serum P53 and Caspase 3 levels in non-athlete men (24). One primary hypothesis for apoptosis due to intense exercise is the increased production of ROS from heightened metabolism. Elevated reactive oxygen species can directly cause DNA damage and apoptosis (25). Although ROS indices were not measured in this study, the high intensity of resistance training (up to 180% of body weight) may have increased ROS and Caspase 3 expression in Wistar rats. The results of Jookar and colleagues (2021) were not aligned with this study, as they found no significant change in Caspase 3 content in diabetic mice after high-intensity interval training compared to the control group. They suggested that training reduced P53 protein content and inhibited Caspase 3 activation, likely deactivating the apoptosis pathway in cardiac cells of type 1 diabetic mice (26). Similarly, Huang and colleagues (2016) showed that 10 weeks of physical training inhibited Fas-dependent and mitochondria-dependent apoptosis pathways in ovariectomized mice, significantly reducing Fas ligand, Caspase 8, |
releasing apoptosis-inducing factors like cytochrome C and Caspases (32, 33). Various factors, such as TNFα and the renin-angiotensin-aldosterone system (RAAS), activate extrinsic and intrinsic apoptosis pathways, with the angiotensin-converting enzyme 2 (ACE2) playing a key role (34). A study linked ACE2, TNFα, and Caspase 3, showing that testosterone, ACE2, and TNF-α interactions in cultured cardiac myocytes induce apoptosis in a dose-dependent manner .
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Funding This study did not have any funds. |
Compliance with ethical standards |
Conflict of interest None declared. Ethical approval the research was conducted with regard to the ethical principles. Informed consent Informed consent was obtained from all participants.
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Conclusion
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Author contributions
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lthough high-intensity resistance training did not significantly alter Caspase 3 gene expression, a non-significant increase was observed compared to the control group, possibly due to ROS production. However, exercise + testosterone significantly increased Caspase 3 expression, indicating enhanced apoptosis in Wistar rat heart tissue. This suggests that supraphysiological doses of testosterone enanthate with resistance training may increase apoptosis risk, potentially leading to cardiomyopathy and severe cardiac damage. It is recommended to raise awareness among young people, especially athletes, about the risks of combining steroids with resistance training.
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Conceptualization: A.B., A.G.; Methodology: R.G., S.A.; Software: A.B., R.G., A.G.; Validation: S.A., A.B.; Formal analysis: A.B., A.G; Investigation S.A., A.B., Resources: R.G.; Data curation: A.B., A.G; Writing - original draft: H.S., S.R.; Writing - review & editing: A.B., R.G., A.G.; Visualization: A.B.; Supervision: A.B.; Project administration: A.G.; Funding acquisition: A.B., R.G.
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Acknowledgements |
This article is derived from a doctoral dissertation. The authors express gratitude to all those who contributed to this research. |
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