Introduction

Breast cancer is the most common cancer in women, usually due to the abnormal growth and division of different breast cells.¹ Breast cancer is a malignant tumor that starts in the breast cells and is able to spread (metastasize) and can actually attack the surrounding tissues.² The first complication in a person with breast cancer is inflammation in the area of the tumor and cancerous tissues. Inflammation both plays a key role in tumor development in breast cancer and affects tumor proliferation, angiogenesis, metastasis, and resistance to treatment. The main features of cancer related inflammation include leukocyte infiltration, cytokine production, tissue remodeling, and angiogenesis.²

Obesity and insulin resistance are both known risk factors for breast cancer and are associated with late stage disease and poor prognosis.³ Obesity and overweight appear to play a role in insulin resistance by increasing inflammatory markers as well as the production of cytokines secreted by various tissues, including adipokines.⁴ The International Agency for Research on Cancer estimates that 25% of the causes of cancer are obesity or overweight and sedentary lifestyle.^5,6 Weight gain of 1.5 times the normal range increases the risk of breast cancer. In particular, weight gain after the age of eighteen significantly increases the risk of developing this cancer and there is a significant relationship between high body mass index and breast cancer, especially in the postmenopausal period^7,8 Inactivity is also an effective factor in insulin resistance.⁹

Myostatin, a myokin known to inhibit skeletal muscle growth, has been linked to the development of insulin resistance. However, little is known about the regulation of myostatin in human obesity and insulin resistance.¹⁰ Research on cancer patients has shown that myostatin is a new tumor causing agent that causes cachexia in these patients.¹¹ In this regard, Lokireddy et al.; ¹¹ Costelli et al.¹² and Aversa et al.¹³ reported the role of myostatin signaling in reducing muscle mass in cancer.

One of the factors affecting body composition is lifestyle. Therefore, researchers study physical activity as an effective factor on physiological and anthropometric function in women with breast cancer.⁶ Previous research has shown that one of the most important non-pharmacological interventions that can help improve the quality of life of cancer patients is exercise.^14,15The benefits of exercise have been confirmed for patients with breast cancer, and physical inactivity can increase the risk of breast cancer by 2 to 5 times.¹⁶ Exercise may also reduce many of the side effects of cancer treatment, including chemotherapy and radiation therapy.¹⁷ In fact, one of the reasons for recommending exercise activities for cancer survivors is that the numerous biotoxicities that occur in the body during cancer treatment are favorably neutralized by exercise activities.¹⁸ In this regard, Irwin et al. showed that the risk of death from breast cancer is reduced by 45% in women who were physically active before the diagnosis but then exercised.¹⁹

Resistance training is a strong stimulus for increasing the size of muscle fibers and hypertrophy, in which myostatin changes play a role in regulating muscle growth.²⁰ Considering that resistance training is a non-pharmacological solution to maintain body muscle mass in cancer patients²¹, this style of exercise can be used to treat and reduce the side effects of cancer treatment such as chemotherapy. Efforts to achieve enhancement of muscle strength and muscle hypertrophy throughout the training path are related to the period of the training program in which the muscles adapt to the training. Exercise trainers use training schedules and changes in training intensity and volume during training sessions to find the solution to find the fastest path to hypertrophy in the training program.²² In fact, training periodization is one of these variables that can affect training results and adaptations. Training periodization is the manipulation and regular changes in the training process to develop training adaptation and avoid the phase of incompatibility and uniformity of training responses. Although there are different models of workout periodization, two types of traditional or linear periodization and nonlinear or wave periodization are more commonly used. In linear periodization the volume of training decreases as the intensity of training increases linearly throughout the training program. But in nonlinear or wave periodization, Intensity and volume of training alternate daily or weekly^23,24 Linear periodization is a classic type of periodization in which the intensity of the exercise is gradually increased, resulting in a reduction in the volume of exercise within and between the exercise cycles. Nonlinear periodization is characterized by frequent changes in training intensity and volume during the training period. In this timing style, instead of changing the intensity of the exercise during a training period, they make these changes on a weekly or even daily basis. Given that the purpose of scheduling is to create metabolic fatigue, mechanical overload, or a combination of both, which allows for optimal flexibility over a long period of training by manipulating training stimuli?²²

Given that insulin resistance is associated with body composition and obesity and myostatin is a myokine associated with muscle mass;^3,13 It is important to examine the changes in these variables in intervention programs in the treatment of breast cancer. The need for this study justifies the need for the present study, which has not specifically studied the effect of nonlinear resistance training on insulin resistance and myostatin levels in women with breast cancer.

According to the above, the aim of this study was to compare the effect of nonlinear resistance training on insulin resistance and serum myosatin level in women with breast cancer.

Methodology

In the present quasi experimental study, 20 women with breast cancer referred to Imam Hassan Chemotherapy and Radiotherapy Center in Dezful, Iran were selected by random sampling method. Criteria for inclusion in this study include definitive diagnosis of breast cancer by an oncologist, disease level 1-2, chemotherapy intervention, no pain and fatigue and declaration of readiness to cooperate, no severe vision and hearing problems, age range 50-40 years and light Life was inactive (maximum oxygen consumption was less than 40 ml/kg/min). Exclusion criteria included dissatisfaction with participation in the research project, failure to follow the exercise intervention program, having periods of pain and fatigue during the training and patient death. After selecting the research samples in an educational session that was conducted jointly with the presence of the nurse and tips about educational services, issues such as how to use the drug, side effects of taking the drug, scheduling the use of drugs by introducing centers that provide medical services to patients were educated. In addition to the training tips provided by the nurse, tips on the research design and how to participate in it were presented to patients by the researcher, and after signing the informed consent, a schedule for physiological tests and blood sampling was coordinated. Then, the subjects were randomly divided into 3 groups: Linear resistance training, nonlinear resistance training and control group. In this study, exercise intervention included a resistance training program with non-linear periodization for patients with breast cancer, which included 12 weeks of training with 3 training sessions per week. Exercise workout included seated leg extension, leg curl, dumbbell chest press, incline dumbbell chest press, sitting rowing, dead lift, and abdominal crunch, lat pull down, back thigh, dumbbell shoulder press, biceps barbell and triceps barbell. Based on nonlinear resistance training, it has been suggested by Kramer and Fleck.²⁵ The implementation of the training program in the nonlinear schedule is such that the intensity of training in training sessions is different (Tables 1-4). The intensity of the exercise in the present study will be calculated based on a maximum repetition (1RM) for different movements using Brzezinski formula.²⁶

1RM=Weight ÷ (1.0278-0.0278 × Number of repetitions)

The control group was trained to maintain normal physical activity and leisure and not to participate in any new exercise programs during the research period. After the research intervention period, the control group participants who participated in the baseline measurements and 12 week post-test had the opportunity to participate in a program similar to the training group.

Before the intervention, training was performed to evaluate blood variables in patients. Blood sampling was performed at a specific time of 7-8 in the morning and fasting (8-10 hours of night fasting). Due to the fact that physical activity may affect the level of blood variables, the subjects were told not to do strenuous exercise on the day before blood sampling and if so, the researcher must be informed. Blood samples were taken 48 hours after the last training session to assess the research variables for the post test.

Fasting serum glucose were measured by kits (Pars Azmoon ^®, Tehran, Iran) and using the photometric methods and an autoanalyzer (Biotecnica instrument^®, Rome, Italy). The serum fasting insulin levels were assessed by the Enzyme Linked Immunosorbent Assay (ELISA) method and using the human insulin kit (ZellBio^®, Ulm, Germany). HOMA-IR was calculated using the following formula: HOMA-IR=[fasting glucose (mmol/l) × fasting insulin (mU/l)/22.5].

Data were used using descriptive statistical tests (frequency, mean and standard deviation) and Shapirovilk statistical tests to check the normality of information and Leven test to check the homogeneity of variances. Analysis of covariance was used to analyse the differences between groups and statistical analysis was performed using SPSS software version ²⁶ and a significance level of P ≤ 0.05.

Results and Discussion

The results of paired sample t-test showed a significant decrease in body fat percentage (P<0.001), serum myostatin level (P=0.002), fasting insulin (P<0.001), and insulin resistance index (P<0.001) in the ratio exercise group. Baseline values were observed but no significant differences were observed in weight, body mass index and fasting glucose (P>0.05); In the control group, no significant differences were observed compared to the baseline values in any of the research variables (P>0.05). Also, in the study of intergroup changes, the results of analysis of covariance showed that changes in body fat percentage (P=0.038), serum myostatin level (P=0.023), fasting insulin (P<0.001), and insulin resistance index (P<0.001) It was significant in the exercise group compared to the control group.

The results of the present study showed that after the training period, a significant reduction in insulin resistance and body fat percentage was observed. Bruno et al. Also reported that aerobic exercise plays a positive role in reducing insulin resistance in women with breast cancer by improving body composition.²⁷ Chang et al. Also reported in their study that after a period of combined aerobic and resistance training, in addition to increasing physical fitness, a significant improvement in insulin sensitivity was observed in women with breast cancer.²⁸ The results of this study were consistent with the improvement in insulin resistance in our study. Regarding the effect of exercise on glucose uptake, it can be said that one session of physical activity stimulates glucose uptake through the up regulation of exercise on GLUT4 levels in skeletal muscle membranes. This effect is independent of insulin and glucose uptake continues for several hours after the end of physical activity. Physical activity also increases insulin sensitivity in skeletal muscle. This effect lasts for several hours after the end of physical activity and is clearly dependent on insulin and insulin function.²⁹ Regarding the chronic effect of regular exercise on insulin resistance, it can be said that exercise training by increasing cell sensitivity with insulin dependent molecular pathways that improve insulin signaling (ACC and MAPKs PI3-kinase) as well as insulin independent pathways (Akt and mTOR AMP-kinase), are involved in improving insulin signaling as well as better glucose uptake.^9,29

Also, in our study, a significant decrease in serum myostatin level was observed after the period of nonlinear resistance training; which was in line with the reduction in body fat percentage as well as insulin resistance. Previous research has shown that resistance exercise has an effective role in improving body composition and reducing insulin resistance is associated with weight loss and a decrease in body fat percentage;^30,31 Myostatin is a myokine associated with muscle mass¹³ and insulin resistance¹⁰ that is more concentrated in women with breast cancer than in healthy women.³² It seems that the decrease in serum myostatin in the present study is due to the effects of resistance training on reducing body fat percentage as well as insulin resistance in women with breast cancer. The effects of myostatin on glucose metabolism may be due to the effects on muscle tissue itself, as only inhibition of myostatin signaling in skeletal muscle, not fat, indicates an improvement in insulin sensitivity.³³ According to myostatin, myostatin is an inhibitor of muscle growth¹⁰ and on the other hand, resistance training is a muscle stress for hypertrophy that is adapted by inhibiting myostatin,³⁴it can be said that part of the effects Insulin resistance training is associated with changes in glucose metabolism in muscle, which may be associated with decreased serum myostatin.³³

Conclusion

Our study was the first randomized controlled trial to investigate the effects of resistance training with nonlinear timing of insulin resistance and serum myostatin levels as a biomarker associated with breast cancer associated with insulin resistance and obesity as two associated complications. Overall, the results of the present study showed that a 12 week period of regular resistance training with nonlinear timing reduced body fat percentage and insulin resistance in women with breast cancer. The results of our research also indicate the beneficial role of resistance training in reducing serum myostatin as a biomarker associated with cachexia due to cancer, which is also associated with obesity as well as insulin resistance. Given that the complications of breast cancer are associated with obesity as well as insulin resistance, the clinical effects of resistance training on women with breast cancer can be considered useful; therefore, it is recommended that women with breast cancer use a resistance training program to reduce the complications of cancer and the treatments associated with this disease.

Appreciation

The authors thank the Imam Hassan (AS) Chemotherapy and Radiotherapy Centre in Dezful, the participating patients and all those who contributed to the present study.

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