Nutritional and Contractile Regulation of Muscle Growth

Study Overview
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Brief Summary
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Muscle wasting, which involves the loss of muscle tissue, is common in many conditions, such as cancer, AIDS, trauma, kidney failure, bone fracture, and sepsis. It is also prevalent among the elderly and in people who experience periods of physical inactivity and weightlessness. Muscle wasting can lead to overall weakness, immobility, physical dependence, and a greater risk of death when exposed to infection, surgery, or trauma. There is a need to develop scientifically based treatments that prevent muscle wasting. As one step towards such a goal, this study will examine the physiological and cellular mechanisms that regulate skeletal muscle growth.

Detailed Description
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Skeletal muscle comprises about 40% of one's body weight and contains about 50% to 75% of all the proteins in the human body. The turnover of protein is a regular process in the human body. In healthy adults, the interplay between muscle protein synthesis and muscle protein breakdown results in no net growth or loss of muscle mass. But when the scale tips towards muscle protein breakdown, muscle wasting can occur. This can result in negative consequences, because not only does muscle fill the obvious role of converting chemical energy into mechanical energy for moving and maintaining posture, but muscle is also involved in the following less apparent roles: regulating metabolism; removing potentially toxic substances from blood circulation; producing fuel for other tissues; storing energy and nitrogen, both of which are important for fueling the brain and immune system; and facilitating wound healing during malnutrition, starvation, injury, and disease. Therefore, muscle is important not only for physical independence but also for mere survival of the human body. In fact, a mere 30% loss of the body's proteins results in impaired respiration and circulation and can eventually lead to death. The purpose of this study is to examine the physiological and cellular mechanisms that regulate skeletal muscle growth. Results from the study may help to develop future treatments for maintaining and possibly increasing muscle mass as a way to improve function, reduce disease complications, and increase survival. This study will enroll healthy participants who will be randomly assigned to one of several treatment arms within one of three separate experiments. Overall, the three experiments will examine the following: (1) whether the mammalian target of rapamycin (mTOR) signaling pathway--a group of molecules that work together to control a specific cellular function--is responsible for stimulating muscle protein synthesis after resistance exercise and/or ingestion of an amino acid supplement; (2) whether restricting blood flow with a blood pressure cuff during low-intensity resistance exercise ultimately leads to muscle protein synthesis; and (3) whether aging is associated with reduced physiological and cellular mechanisms that are related to muscle protein synthesis and whether such a reduction can be overcome by post-exercise ingestion of an amino acid supplement or blood flow restriction during low-intensity resistance exercise. Depending on which treatment arm participants are assigned to, they may receive amino acid supplementation, the drug rapamycin, the drug sodium nitroprusside, and/or placebo. They may also undergo high-intensity resistance exercise, low-intensity resistance exercise, or low-intensity resistance exercise along with blood flow restriction. All participants will attend a single 8-hour study visit and a follow-up visit 1 week later. During the study visit, participants will undergo the following: measurements of vital signs, height, and weight; blood and urine sampling; a dual energy x-ray absorptiometry (DEXA) scan; and an infusion study that will include additional blood sampling, muscle biopsies, and assigned interventions. The follow-up visit will include evaluation of any incisions that were made during the infusion study.

Official Title
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Nutritional and Contractile Regulation of Muscle Growth (Cycle 2)

Conditions
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Sarcopenia

Intervention / Treatment
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* Drug: Rapamycin
* Other: Amino acid supplementation
* Other: Low-intensity resistance exercise
* Drug: Sodium nitroprusside
* Device: Blood flow restriction cuff
* Other: Low-intensity resistance exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 35 years of age for the young groups 60 to 85 years of age for the older groups In the follicular phase for the young women participants Ability to sign consent form, as based on a score of greater than 25 on the 30-item Mini Mental State Examination (MMSE) Stable body weight for at least 1 year Exclusion Criteria: Physical dependence or frailty, as determined by impairment in any of the activities of daily living (ADLs), history of more than two falls per year, or significant weight loss in the past year Exercise training that consists of more than two weekly sessions of moderate to high intensity aerobic or resistance exercise Significant heart, liver, kidney, blood, or respiratory disease Peripheral vascular disease Diabetes mellitus or other untreated endocrine disease Active cancer History of cancer for participants who may be randomly assigned to rapamycin) Acute infectious disease or history of chronic infections (e.g., tuberculosis, hepatitis, HIV, herpes) Treatment with anabolic steroids or corticosteroids within 6 months of study entry Alcohol or drug abuse Tobacco use (smoking or chewing) Malnutrition (e.g., body mass index [BMI] less than 20 kg/m2, hypoalbuminemia, and/or hypotransferrinemia) Obesity (BMI greater than 30 kg/m2) Lower than normal hemoglobin levels

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

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: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Exp 1: AA + Rap<br>Participants will receive amino acid supplementation and rapamycin. | Drug: Rapamycin<br>* Single 16-mg oral dose<br>Other: Amino acid supplementation<br>* Nutritional drink containing essential amino acids<br>|
| Placebo Comparator: Exp 1: AA<br>Participants will receive amino acid supplementation and placebo rapamycin. | Other: Amino acid supplementation<br>* Nutritional drink containing essential amino acids<br>|
| Active Comparator: Exp 1: HEx + Rap<br>Participants will receive rapamycin and placebo amino acid supplementation, and they will undergo high-intensity resistance exercise. | Drug: Rapamycin<br>* Single 16-mg oral dose<br>Other: Low-intensity resistance exercise<br>* Leg extension exercises on a Cybex leg extension machine<br>|
| Placebo Comparator: Exp 1: HEx<br>Participants will receive placebo amino acid supplementation and placebo rapamycin, and they will undergo high-intensity resistance exercise. | Other: Low-intensity resistance exercise<br>* Leg extension exercises on a Cybex leg extension machine<br>|
| Active Comparator: Exp 1: HEx + AA + Rap<br>Participants will receive amino acid supplementation and rapamycin, and they will undergo high-intensity resistance exercise. | Drug: Rapamycin<br>* Single 16-mg oral dose<br>Other: Amino acid supplementation<br>* Nutritional drink containing essential amino acids<br>Other: Low-intensity resistance exercise<br>* Leg extension exercises on a Cybex leg extension machine<br>|
| Placebo Comparator: Exp 1: HEx + AA<br>Participants will receive amino acid supplementation and placebo rapamycin, and they will undergo high-intensity resistance exercise. | Other: Amino acid supplementation<br>* Nutritional drink containing essential amino acids<br>Other: Low-intensity resistance exercise<br>* Leg extension exercises on a Cybex leg extension machine<br>|
| Active Comparator: Exp 2: LExFR + Rap<br>Participants will receive rapamycin and will undergo low-intensity resistance exercise with blood flow restriction. | Drug: Rapamycin<br>* Single 16-mg oral dose<br>Device: Blood flow restriction cuff<br>* Blood flow restriction for 5 minutes after the second biopsy<br>* Other names: KAATSU cuff;Other: Low-intensity resistance exercise<br>* Leg extension exercises on a Cybex leg extension machine<br>|
| Placebo Comparator: Exp 2 and 3: LExFR<br>Participants will receive placebo rapamycin and will undergo low-intensity resistance exercise with blood flow restriction. | Device: Blood flow restriction cuff<br>* Blood flow restriction for 5 minutes after the second biopsy<br>* Other names: KAATSU cuff;Other: Low-intensity resistance exercise<br>* Leg extension exercises on a Cybex leg extension machine<br>|
| Active Comparator: Exp 2: SNP<br>Participants will receive sodium nitroprusside in a resting state. | Drug: Sodium nitroprusside<br>* Variable rate for 3 hours<br>|
| Active Comparator: Exp 2: FR<br>Participants will undergo blood flow restriction in a resting state. | Device: Blood flow restriction cuff<br>* Blood flow restriction for 5 minutes after the second biopsy<br>* Other names: KAATSU cuff;|
| Active Comparator: Exp 2: LEx + SNP<br>Participants will receive sodium nitroprusside and undergo low-intensity resistance exercise. | Drug: Sodium nitroprusside<br>* Variable rate for 3 hours<br>Other: Low-intensity resistance exercise<br>* Leg extension exercises on a Cybex leg extension machine<br>|
| Placebo Comparator: Exp 3: LEx<br>Participants will undergo low-intensity resistance exercise. | Other: Low-intensity resistance exercise<br>* Leg extension exercises on a Cybex leg extension machine<br>|
| Active Comparator: Exp 3: HEx<br>Participants will undergo high-intensity resistance exercise. | Other: Low-intensity resistance exercise<br>* Leg extension exercises on a Cybex leg extension machine<br>|
| Active Comparator: Exp 3: HEx + AA<br>Participants will receive amino acid supplementation and will undergo high-intensity resistance exercise. | Other: Low-intensity resistance exercise<br>* Leg extension exercises on a Cybex leg extension machine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle protein synthesis |  | Measured during the 8-hour infusion study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phosphorylation status of mTOR signaling proteins |  | Measured during the 8-hour infusion study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sarcopenia, Aging, Metabolism, Muscle, mTOR, Essential Amino Acids, Exercise, Rapamycin