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Nutritional and Contractile Regulation of Muscle Growth

Primary Purpose

Sarcopenia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Rapamycin
Amino acid supplementation
Low-intensity resistance exercise
Sodium nitroprusside
Blood flow restriction cuff
Low-intensity resistance exercise
Sponsored by
The University of Texas Medical Branch, Galveston
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Sarcopenia focused on measuring Sarcopenia, Aging, Metabolism, Muscle, mTOR, Essential Amino Acids, Exercise, Rapamycin

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Department of Nutrition & Metabolism, University of Texas Medical Branch

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm 13

Arm 14

Arm Type

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Active Comparator

Active Comparator

Active Comparator

Placebo Comparator

Active Comparator

Active Comparator

Arm Label

Exp 1: AA + Rap

Exp 1: AA

Exp 1: HEx + Rap

Exp 1: HEx

Exp 1: HEx + AA + Rap

Exp 1: HEx + AA

Exp 2: LExFR + Rap

Exp 2 and 3: LExFR

Exp 2: SNP

Exp 2: FR

Exp 2: LEx + SNP

Exp 3: LEx

Exp 3: HEx

Exp 3: HEx + AA

Arm Description

Participants will receive amino acid supplementation and rapamycin.

Participants will receive amino acid supplementation and placebo rapamycin.

Participants will receive rapamycin and placebo amino acid supplementation, and they will undergo high-intensity resistance exercise.

Participants will receive placebo amino acid supplementation and placebo rapamycin, and they will undergo high-intensity resistance exercise.

Participants will receive amino acid supplementation and rapamycin, and they will undergo high-intensity resistance exercise.

Participants will receive amino acid supplementation and placebo rapamycin, and they will undergo high-intensity resistance exercise.

Participants will receive rapamycin and will undergo low-intensity resistance exercise with blood flow restriction.

Participants will receive placebo rapamycin and will undergo low-intensity resistance exercise with blood flow restriction.

Participants will receive sodium nitroprusside in a resting state.

Participants will undergo blood flow restriction in a resting state.

Participants will receive sodium nitroprusside and undergo low-intensity resistance exercise.

Participants will undergo low-intensity resistance exercise.

Participants will undergo high-intensity resistance exercise.

Participants will receive amino acid supplementation and will undergo high-intensity resistance exercise.

Outcomes

Primary Outcome Measures

Muscle protein synthesis

Secondary Outcome Measures

Phosphorylation status of mTOR signaling proteins

Full Information

First Posted
April 29, 2009
Last Updated
May 1, 2017
Sponsor
The University of Texas Medical Branch, Galveston
Collaborators
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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1. Study Identification

Unique Protocol Identification Number
NCT00891696
Brief Title
Nutritional and Contractile Regulation of Muscle Growth
Official Title
Nutritional and Contractile Regulation of Muscle Growth (Cycle 2)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2015
Overall Recruitment Status
Completed
Study Start Date
April 2009 (undefined)
Primary Completion Date
March 2015 (Actual)
Study Completion Date
March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The University of Texas Medical Branch, Galveston
Collaborators
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sarcopenia
Keywords
Sarcopenia, Aging, Metabolism, Muscle, mTOR, Essential Amino Acids, Exercise, Rapamycin

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Factorial Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
144 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Exp 1: AA + Rap
Arm Type
Active Comparator
Arm Description
Participants will receive amino acid supplementation and rapamycin.
Arm Title
Exp 1: AA
Arm Type
Placebo Comparator
Arm Description
Participants will receive amino acid supplementation and placebo rapamycin.
Arm Title
Exp 1: HEx + Rap
Arm Type
Active Comparator
Arm Description
Participants will receive rapamycin and placebo amino acid supplementation, and they will undergo high-intensity resistance exercise.
Arm Title
Exp 1: HEx
Arm Type
Placebo Comparator
Arm Description
Participants will receive placebo amino acid supplementation and placebo rapamycin, and they will undergo high-intensity resistance exercise.
Arm Title
Exp 1: HEx + AA + Rap
Arm Type
Active Comparator
Arm Description
Participants will receive amino acid supplementation and rapamycin, and they will undergo high-intensity resistance exercise.
Arm Title
Exp 1: HEx + AA
Arm Type
Placebo Comparator
Arm Description
Participants will receive amino acid supplementation and placebo rapamycin, and they will undergo high-intensity resistance exercise.
Arm Title
Exp 2: LExFR + Rap
Arm Type
Active Comparator
Arm Description
Participants will receive rapamycin and will undergo low-intensity resistance exercise with blood flow restriction.
Arm Title
Exp 2 and 3: LExFR
Arm Type
Placebo Comparator
Arm Description
Participants will receive placebo rapamycin and will undergo low-intensity resistance exercise with blood flow restriction.
Arm Title
Exp 2: SNP
Arm Type
Active Comparator
Arm Description
Participants will receive sodium nitroprusside in a resting state.
Arm Title
Exp 2: FR
Arm Type
Active Comparator
Arm Description
Participants will undergo blood flow restriction in a resting state.
Arm Title
Exp 2: LEx + SNP
Arm Type
Active Comparator
Arm Description
Participants will receive sodium nitroprusside and undergo low-intensity resistance exercise.
Arm Title
Exp 3: LEx
Arm Type
Placebo Comparator
Arm Description
Participants will undergo low-intensity resistance exercise.
Arm Title
Exp 3: HEx
Arm Type
Active Comparator
Arm Description
Participants will undergo high-intensity resistance exercise.
Arm Title
Exp 3: HEx + AA
Arm Type
Active Comparator
Arm Description
Participants will receive amino acid supplementation and will undergo high-intensity resistance exercise.
Intervention Type
Drug
Intervention Name(s)
Rapamycin
Intervention Description
Single 16-mg oral dose
Intervention Type
Other
Intervention Name(s)
Amino acid supplementation
Intervention Description
Nutritional drink containing essential amino acids
Intervention Type
Other
Intervention Name(s)
Low-intensity resistance exercise
Intervention Description
Leg extension exercises on a Cybex leg extension machine
Intervention Type
Drug
Intervention Name(s)
Sodium nitroprusside
Intervention Description
Variable rate for 3 hours
Intervention Type
Device
Intervention Name(s)
Blood flow restriction cuff
Other Intervention Name(s)
KAATSU cuff
Intervention Description
Blood flow restriction for 5 minutes after the second biopsy
Intervention Type
Other
Intervention Name(s)
Low-intensity resistance exercise
Intervention Description
Leg extension exercises on a Cybex leg extension machine
Primary Outcome Measure Information:
Title
Muscle protein synthesis
Time Frame
Measured during the 8-hour infusion study
Secondary Outcome Measure Information:
Title
Phosphorylation status of mTOR signaling proteins
Time Frame
Measured during the 8-hour infusion study

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Blake Rasmussen, PhD
Organizational Affiliation
The University of Texas Medical Branch, Galveston
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Nutrition & Metabolism, University of Texas Medical Branch
City
Galveston
State/Province
Texas
ZIP/Postal Code
77550
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
18535123
Citation
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Volpi E, Chinkes DL, Rasmussen BB. Sequential muscle biopsies during a 6-h tracer infusion do not affect human mixed muscle protein synthesis and muscle phenylalanine kinetics. Am J Physiol Endocrinol Metab. 2008 Oct;295(4):E959-63. doi: 10.1152/ajpendo.00671.2007. Epub 2008 Aug 19.
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Dreyer HC, Drummond MJ, Glynn EL, Fujita S, Chinkes DL, Volpi E, Rasmussen BB. Resistance exercise increases human skeletal muscle AS160/TBC1D4 phosphorylation in association with enhanced leg glucose uptake during postexercise recovery. J Appl Physiol (1985). 2008 Dec;105(6):1967-74. doi: 10.1152/japplphysiol.90562.2008. Epub 2008 Oct 9.
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Graber TG, Borack MS, Reidy PT, Volpi E, Rasmussen BB. Essential amino acid ingestion alters expression of genes associated with amino acid sensing, transport, and mTORC1 regulation in human skeletal muscle. Nutr Metab (Lond). 2017 May 11;14:35. doi: 10.1186/s12986-017-0187-1. eCollection 2017. Erratum In: Nutr Metab (Lond). 2017 Jun 14;14 :39.
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Dickinson JM, Gundermann DM, Walker DK, Reidy PT, Borack MS, Drummond MJ, Arora M, Volpi E, Rasmussen BB. Leucine-enriched amino acid ingestion after resistance exercise prolongs myofibrillar protein synthesis and amino acid transporter expression in older men. J Nutr. 2014 Nov;144(11):1694-702. doi: 10.3945/jn.114.198671. Epub 2014 Sep 3.
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Dickinson JM, Drummond MJ, Fry CS, Gundermann DM, Walker DK, Timmerman KL, Volpi E, Rasmussen BB. Rapamycin does not affect post-absorptive protein metabolism in human skeletal muscle. Metabolism. 2013 Jan;62(1):144-51. doi: 10.1016/j.metabol.2012.07.003. Epub 2012 Sep 6.
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Nutritional and Contractile Regulation of Muscle Growth

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