The Effect of Blood Flow Restriction (Bfr) Exercise on Acute Systemic Myokine Levels in Healthy Trained Men

Study Overview
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Brief Summary
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The aim of the study is to measure and compare acute systemic irisin, myostatin and decorin levels after a single session of blood flow restricted resistance exercise and resistance exercise without blood flow restriction in healthy, trained male participants aged 18-35 years. For this purpose, a total of 22 people will be included in the study. Participants will be randomly allocated to 2 exercise groups as resistance exercise with blood flow restriction (BFR-RE) and resistance exercise without blood flow restriction (HL-RE) and will be subjected to cross-over. In the HL-RE intervention, the exercise will be performed with a loading of 80% of 1 RM, with 4 sets x 7 repetitions, with 60 seconds of rest between sets. In the BFR-RE intervention, the exercise will be done as a set of 30 repetitions with a loading of 30% of 1 RM and an additional 3 sets x 15 repetitions, with 30 seconds rest between sets. Total exercise volumes were tried to be equalized and skeletal muscle hypertrophy was selected in accordance with exercise guidelines. In both groups, bilateral leg extension exercise will be performed using the leg extension machine for resistance exercise. In the blood flow restriction group (BFR-RE), the cuff will be placed in the proximal region of the thigh bilaterally, inflated to a pressure equivalent to 50% of the estimated arterial occlusion pressure (AOP), and leg extension exercise will be performed under this condition. In the BFR-RE group, the blood flow restriction time will be between 5-10 minutes. Exercise sessions will be conducted under supervision. Venous blood samples will be collected from the arm antecubital region of the participants just before the exercise session, immediately after the exercise, and 1 hour after the exercise. Plasma irisin, myostatin and decorin levels will be measured from the samples taken. It is well known that resistance exercise is important in maintaining and increasing muscle mass (hypertrophy). Studies have shown the involvement of certain myokines in skeletal muscle hypertrophy, although few studies have been conducted on the systemic response of myokines to BFR-RE that may play a potential role in hypertrophy. Therefore, the planned study aimed to reveal the similarities or differences in the systemic myokine response between BFR-RE and HL-RE.

Detailed Description
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Resistance exercise is a type of exercise classically used to increase skeletal muscle hypertrophy and muscle strength. Resistance training is an important component of training in most sports, and it also plays a role in injury prevention and rehabilitation. In dynamic resistance exercise, the intensity is usually determined by measuring the maximum weight that can be lifted only once (one repetition maximum, 1RM). The American College of Sports Medicine (ACSM) recommends more than 70% of 1RM to increase muscle mass (high load resistance exercise, HL-RE). High-intensity loads recommended by the ACSM may not be a suitable option for populations with sarcopenia, the elderly with chronic health conditions, or those with injuries that cannot tolerate heavy load, as they create excessive mechanical stress on the tissues during exercise and pose a potential risk of injury. There is increasing evidence that the use of blood flow restriction (BFR), also known as occlusion or Kaatsu training, with low-load resistance exercise (<50% 1RM) provides hypertrophic gains. This training method (BFR RE) is an exercise method performed by placing an inflatable cuff on the proximal part of the extremity (arm or leg) to restrict blood flow and restricting venous return distal to the obstruction without obstructing arterial flow. As publications using this method increase, interest in BFR-RE has increased to increase skeletal muscle hypertrophy and strength in athletes, the elderly, or clinical populations (such as cerebrovascular, cardiac, neuromuscular diseases, obesity). Standard hypertrophy exercise parameters consist of 1-3 total sets, 8-12 repetitions for sets, and 1-2 minutes rest between sets, with a loading of 70-85% of 1RM in beginner-intermediate levels. BFR-RE, on the other hand, consists of a loading interval of 20-40% of 1RM, a set of 30 repetitions, followed by 3 additional sets of 15 repetitions, with 30 seconds of rest between sets. Despite this difference in exercise protocols, both approaches provide skeletal muscle hypertrophy. Studies show that low-load-high-rep resistance exercises, when performed until fatigue, cause skeletal muscle hypertrophy similar to high-load-low-rep resistance exercises. In addition, BFR-RE is superior to unrestricted low-load resistance exercise in terms of skeletal muscle hypertrophy when the exercise volume is equalized. According to a meta-analysis, BFR-RE has been shown to induce increases in muscle mass comparable to HL-RE regardless of absolute occlusion pressure, cuff width, and method of generating occlusion pressure. Although the potent hypertrophic effects of BFR-RE have been demonstrated by numerous studies, the underlying mechanisms responsible for such effects are not well defined. Although the potent hypertrophic effects of BFR-RE have been demonstrated by numerous studies, the underlying mechanisms responsible for such effects are not well defined. Metabolic stress (accumulation of metabolites as a result of the ischemic/hypoxic environment) has been suggested to be the primary responsible factor, and is thought to activate numerous other mechanisms thought to induce muscle hypertrophy through autocrine and/or paracrine actions. Secondary mechanisms activated by metabolic stress include involvement of fast twitch muscle fibers (type 2 fibers), release of certain hormones (GH, IGF-1), myokine production, production of reactive oxygen products and cell swelling. However, it is important to recognize that some of these mechanisms are largely induced not by metabolic stress but rather by mechanical tension (another primary factor of muscle hypertrophy). Given that mechanical strain is typically low (<50% 1RM) in BFR-RE, the extent of its involvement in hypertrophic adaptations is questionable. However, mechanical tension and metabolic stress, which are ultimately the primary factors responsible for hypertrophy, act synergistically to produce muscle hypertrophy in BFR-RE. Cytokines are a large family of polypeptides and proteins that function as intercellular messengers. While their primary function is typically associated with immune response, many cytokines appear to exhibit functional pleiotropy. A cytokine may mediate different effects depending on the initial stimulus, the target cell, or other co-released cytokines. Cytokines can also act locally (autocrine or paracrine) or systemically (endocrine) depending on the target tissue. Skeletal muscle has been found to release cytokines in response to muscle contraction. These cytokines, called myokines, have local effects on muscle as well as systemic effects on other tissues. Myokine release after muscle contraction varies according to the intensity, mode and volume of the exercise performed by the person. There are theories that metabolic stress may mediate muscle hypertrophy by upregulating anabolic myokines and/or downregulating catabolic myokines. Irisin was discovered by Bostrom et al in 2012 as a PGC-1α (peroxisome proliferator-activated receptor coactivator 1-alpha)-dependent myokine. It is proteolytically cleaved from the membrane protein FDNC-5 (fibronectin domain-containing protein-5) and secreted from skeletal muscle into the circulation in response to exercise. Irisin is a myokine primarily known for its effect on the conversion of white adipose tissue to brown adipose tissue, thereby increasing thermogenesis and energy metabolism. However, there is new evidence suggesting that the iris may have a role in regulating muscle hypertrophy. Recent studies show that acute intense resistance exercise increases circulating irisin concentrations. It has been reported that irisin induces skeletal muscle hypertrophy and reduces denervation-induced atrophy by activating IL-6 in rodents. It also suggests that irisin may play a role in skeletal muscle hypertrophy by upregulating IGF-1 and downregulating myostatin in human myocyte cultures and in vitro treatment with irisin. Myostatin is a member of the TGF-ß (transforming growth factor-beta) family and acts as a negative regulator of skeletal muscle development. High myostatin levels are significantly associated with muscle wasting diseases, myopathy and sarcopenia. A significant increase in muscle mass was observed in individuals with mutations in both copies of the myostatin gene compared to normal individuals. There are studies showing that myostatin level decreases with a single session of resistance exercise. It has been shown that myostatin levels in the plantaris muscle of rats following blood flow restricted exercise (BFR) were significantly reduced compared to the sham group. Decorin has been defined as another myokine that plays a role in muscle hypertrophy. Myotubes secrete decorin and decorin regulates protein synthesis in vitro. In addition, in vivo evidence from rodent skeletal muscle has shown that overexpression of decorin can upregulate several factors involved in inhibiting myostatin, a potent myokine that decreases muscle cell growth and differentiation and increases protein degradation. It is believed that decorin may be involved in anabolic activity in skeletal muscle by inhibiting myostatin. It has been shown that various acute resistance exercises (LL-RE, HL-RE, BFR-RE) result in a systemic release of decorin, and this myokine may be involved in the hypertrophic response to resistance exercise. There appears to be a lack of research investigating the potential role played by myokines in BFR-RE-induced skeletal muscle hypertrophy. The aim of this study is to evaluate the systemic irisin, myostatin and decorin myokines levels after acute BFR-RE and HL-RE, and to measure whether BFR-RE alters the exercise-induced myokine response. We predict that systemic irisin, myostatin and decorin myokine responses to BFR-RE and HL-RE will be similar.

Official Title
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Effect of Blood Flow Restriction Exercise on Acute Systemic Irisin, Myostatin and Decorin Levels

Conditions
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Muscle Hypotrophy

Intervention / Treatment
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* Other: BFR-RE
* Other: HL-RE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Being between 18-35 years old and male gender To have been doing resistance exercises for at least 1 year and to be accustomed to lower extremity resistance exercises Not doing any resistance exercise with restricted blood flow in the last 1 month Not doing lower extremity resistance exercise for at least 48 hours Answering no to all questions in the Exercise Readiness Questionnaire (EGZ-A+) Exclusion Criteria: Presence of musculoskeletal injury or disability that may prevent exercise with restricted blood flow Using non-steroidal anti-inflammatory drugs (NSAIDs) or supplements that may have an anti-inflammatory effect Being at risk for cardiovascular disease Regular use of tobacco products Using ergogenic support

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BFR-RE<br>In the BFR-RE intervention, the exercise will be done as a set of 30 repetitions with a loading of 30% of 1 RM and an additional 3 sets x 15 repetitions, with 30 seconds rest between sets. | Other: BFR-RE<br>* In the BFR-RE intervention, the exercise will be done as a set of 30 repetitions with a loading of 30% of 1 RM and an additional 3 sets x 15 repetitions, with 30 seconds rest between sets. In both groups, bilateral leg extension exercise will be performed by using the leg extension machine for resistance exercise. In the blood flow restriction group (BFR-RE), the cuff will be placed in the proximal region of the thigh bilaterally, inflated to a pressure equivalent to 50% of the estimated arterial occlusion pressure (AOP), and leg extension exercise will be performed under this condition. In the BFR-RE group, the blood flow restriction time will be between 5-10 minutes. Venous blood samples will be collected from the arm antecubital region of the participants just before the exercise session, immediately after the exercise, and 1 hour after the exercise. Plasma irisin, myostatin and decorin levels will be measured from the samples taken.<br>Other: HL-RE<br>* In the HL-RE intervention, the exercise will be performed with a loading of 80% of 1 RM, with 4 sets x 7 repetitions, with 60 seconds of rest between sets. In both groups, bilateral leg extension exercise will be performed by using the leg extension machine for resistance exercise. Venous blood samples will be collected from the arm antecubital region of the participants just before the exercise session, immediately after the exercise, and 1 hour after the exercise. Plasma irisin, myostatin and decorin levels will be measured from the samples taken.<br>|
| Active Comparator: HL-RE<br>In the HL-RE intervention, the exercise will be performed with a loading of 80% of 1 RM, with 4 sets x 7 repetitions, with 60 seconds of rest between sets. | Other: BFR-RE<br>* In the BFR-RE intervention, the exercise will be done as a set of 30 repetitions with a loading of 30% of 1 RM and an additional 3 sets x 15 repetitions, with 30 seconds rest between sets. In both groups, bilateral leg extension exercise will be performed by using the leg extension machine for resistance exercise. In the blood flow restriction group (BFR-RE), the cuff will be placed in the proximal region of the thigh bilaterally, inflated to a pressure equivalent to 50% of the estimated arterial occlusion pressure (AOP), and leg extension exercise will be performed under this condition. In the BFR-RE group, the blood flow restriction time will be between 5-10 minutes. Venous blood samples will be collected from the arm antecubital region of the participants just before the exercise session, immediately after the exercise, and 1 hour after the exercise. Plasma irisin, myostatin and decorin levels will be measured from the samples taken.<br>Other: HL-RE<br>* In the HL-RE intervention, the exercise will be performed with a loading of 80% of 1 RM, with 4 sets x 7 repetitions, with 60 seconds of rest between sets. In both groups, bilateral leg extension exercise will be performed by using the leg extension machine for resistance exercise. Venous blood samples will be collected from the arm antecubital region of the participants just before the exercise session, immediately after the exercise, and 1 hour after the exercise. Plasma irisin, myostatin and decorin levels will be measured from the samples taken.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in irisin concentrations | It was discovered by Bostrom et al in 2012 as a PGC-1α (peroxisome proliferator-activated receptor coactivator 1-alpha)-dependent myokine. It is proteolytically cleaved from the membrane protein FDNC-5 (fibronectin domain containing protein-5) and secreted from skeletal muscle into the circulation in response to exercise. Irisin is a myokine mainly known for its effect on the conversion of white adipose tissue to brown adipose tissue, thereby increasing thermogenesis and energy metabolism. However, there is new evidence to suggest that the iris may have a role in regulating muscle hypertrophy. | immediately before the exercise session, immediately after the exercise and 1 hour after the exercise | 
| change in myostatin concentrations | It is a member of the TGF-ß (transforming growth factor-beta) family and acts as a negative regulator of skeletal muscle growth. | immediately before the exercise session, immediately after the exercise and 1 hour after the exercise | 
| change in decorin concentrations | It has been identified as another myokine that plays a role in muscle hypertrophy. Decorin is thought to be involved in anabolic activity in skeletal muscle by inhibiting myostatin. | immediately before the exercise session, immediately after the exercise and 1 hour after the exercise | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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blood flow restriction, myokines