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Completed

NCT Number: NCT02261961

Immune Function and Muscle Adaptations to Resistance Exercise in Older Adults

The loss of muscle mass and strength due to aging leads to serious health problems for older adults. Muscle health can be improved by exercise training, but some people improve their strength substantially, whereas others improve little. The reason for this variation is unknown. This study will investigate whether function of the immune system influences how well people respond to exercise. Older Veterans who participate will have their muscle size, strength, and function measured periodically for almost a year. Participants will drink a nutritional supplement or placebo daily and complete a 36 session strength training program. Participants will be vaccinated for tetanus and donate small amounts of blood and muscle tissue during the study so that immune function can be compared to muscle outcomes during training and during a long-term follow-up. The study results should increase the investigators' understanding of the negative effects of aging on muscle and will possibly lead to better strategies for muscle maintenance and rehabilitation for older adults.

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Key information

Conditions

Sarcopenia Aging Atrophy Immune Function Muscular Atrophy Nervous System Diseases Neurologic Manifestations Neuromuscular Manifestations Pathological Conditions, Anatomical Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

60 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Central Arkansas Veterans Healthcare System Eugene J. Towbin Healthcare Center, Little Rock, AR

North Little Rock, Arkansas, 72114-1706, United States

About this study

Objective: The study will examine the influence of immune function in older adults on improvement of muscle mass, strength, and function by resistance training. The maintenance of those benefits during long term follow-up will also be examined. This objective will be accomplished by a double-blind randomized placebo-controlled trial of a nutritional supplement (Muscle Armor) which evidence suggests can improve immune function, promote muscle growth, and counteract muscle loss. The study premise is that aging results in decreased ability of the immune system to respond to stimuli such as exercise. The study proposes that the supplement will improve muscle health by promoting a shift in immune function of older adults from a pro-inflammatory state towards a state which supports muscle growth and maintenance.

Research Plan: The study will randomize Veterans (age 60-80, N=50) to participate in the supplement or placebo groups in a three phase study. The phases of participation correspond to the three specific aims. Aim 1 will determine if 2-weeks of supplementation improves immune function. Humoral immune function will be assessed as the response to vaccination. Innate immune function will be measured as systemic and cellular responses to acute resistance exercise that the investigators' previous studies indicate are affected by aging. Aim 2 will determine if supplementation during 36 sessions of progressive high-intensity resistance training boosts improvement in muscle size (CT scan), strength, and function (gait and balance). Muscle adaptations at the cellular levels will also be measured. Aim 3 will determine if continued supplementation for 26-weeks after completion of exercise training promotes the retention of the gains in muscle size, strength, and function. Multivariable testing will then be used to compare the results between Aims 1, 2, and 3 to determine whether or not immune function is correlated with muscle adaptation to training or detraining.

Methods: Participants will undergo nine blood draws and five muscle biopsies of the vastus lateralis over the course of the study so that the effects of the supplement on immune function and cellular adaptations to training can be measured. Three of the blood draws will be used to assess the antibody response to the tetanus, pertussis, and diphtheria vaccine. Muscle and blood will be collected before and after a bout of exercise conducted before and after the 2-weeks of supplementation prior to training. Immune function will be measured using the blood based on pro- and anti-inflammatory cytokine levels, the balance between specific T-cell subpopulations, and the proliferative capacity of mononuclear cells. Immune function will be measured in muscle based on macrophage content of specific cytokines and growth factors. The investigators' previous study showed that these muscle measures strongly correlate with size and strength gain after training. Key signaling pathways including nuclear factor-k B and PI3 kinase will also be measured. The fifth biopsy will be collected post-training to measure adaptation at the cellular level based on changes in number of satellite cells and myonuclei and fiber size. Hypotheses related to these measures will be tested with 80% power to detect at least 0.8 standard deviations difference in means between the supplement and placebo groups.

Clinical Relevance: Exercise is clearly able to affect immune function. However, the proposed study will attempt to modulate immune function and determine the effects on exercise outcomes. The study will also examine detraining, an important issue for older adults, that is usually omitted from training studies. Thus, the study will potentially advance the understanding of the mechanisms of muscle gain and loss in older adults, but more importantly, the study will evaluate a nutritional intervention as a complement to exercise for supporting muscle health during aging. Targeting the immune system may be the advantage needed for an older Veteran to successfully maintain or restore the muscle mass, strength, and function that is necessary for personal independence.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Veteran
  • Age 60-80 years
  • Body Mass Index of 18.5 - 29.9 kg/m2

Exclusion criteria

  • Currently participating in any other research study involving an intervention
  • Smokes tobacco products
  • Tetanus or TDAP vaccine in previous two years
  • Allergic to vaccination
  • Seizure in past 3 months
  • Guillain-Barre Syndrome in past 3 months
  • Takes the medications heparin, plavix / clopidogrel, or coumadin / warfarin
  • Allergic to lidocaine
  • Significant problem with fainting
  • Problems walking or exercising with both legs
  • Participated in a weight-lifting program targeting the thighs in last 3 months
  • Pains, tightness or pressure in chest during physical activity
  • Metastatic cancer or undergoing chemotherapy
  • Cerebral aneurysm or intracranial bleed in past year
  • End-stage congestive heart failure (NYHA Stage IV)
  • Unstable abdominal or thoracic aortic aneurysm (>4cm)
  • Renal disease requiring dialysis
  • Allergic to vaccination
  • Acute retinal hemorrhage or ophthalmologic surgery in past 3 months
  • Bone fractures in the pelvis, legs, or feet in the last 3 months
  • Hernia that causes pain during physical activity
  • Myocardial infarction or cardiac surgery in past 3 months
  • Pulmonary embolism or deep venous thrombosis in past 3 months
  • Proliferative diabetic retinopathy or severe nonproliferative retinopathy
  • Active suicidality or suicidal ideation
  • Systemic bacterial infection
  • Taking aspirin in any form and unable/unwilling to discontinue at least 10 days prior to muscle biopsy
  • Unwilling to halt concurrent use of amino acid or protein supplements
  • Unwilling to halt new use of nutritional supplements
  • Unwilling to maintain current normal diet
  • Encephalopathy in past 7 days
  • Active oral or genital herpes
  • Current use of appetite stimulants
  • Current treatment for mania or bipolar disorder or taking lithium.
  • Diagnosis of a significant cognitive deficit
  • Untreated severe aortic stenosis
  • Uncontrolled diabetes mellitus (HbA1C>10)
  • Uncontrolled hypertension or hypotension (>160/100, <100 systolic)
  • Uncontrolled malignant cardiac arrhythmia
  • Unstable angina
  • Allergic to latex or tape
  • Bleeding or clotting disorders
  • Taking any non-ASA NSAID and unable or unwilling to discontinue use for 3 days prior to muscle biopsy
  • Taking Fish Oil, Gingko, Garlic, Saw Palmetto, Turmeric, or Vitamin E and unable or unwilling to discontinue use for 10 days prior to the muscle biopsy procedure
  • Significant problems with chronic pain
  • Uncontrolled asthma or allergies
  • Taking lactulose, nitrates plus hypertension medications or Viagra
  • Liver cirrhosis or other severe liver disease
  • History of peripheral artery disease
  • Certain Steroid or androgen use in past 3 months
  • Other physician judgment
  • Significantly abnormal complete blood count (CBC) or prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized ratio (INR)

Treatment and study plan

TDAP

Biological

Both arms will receive the tetanus, diptheria, and pertussis vaccination after two weeks of treatment with supplement or placebo

Other names: tetanus, diptheria, and pertussis vaccination

Acute Resistance Exercise

Other

Both arms will receive a single bout of resistance exercise twice, before and after two weeks of treatment with supplement or placebo, and be evaluated for the response within blood and muscle

Other names: Single bout of exercise

Resistance Exercise Training

Other

Both arms will receive 36 sessions of progressive high-intensity resistance exercise training (thigh muscle) over the course of approximately 12 weeks.

Other names: Chronic exercise

Post-training Follow-up

Other

Both arms will continue to receive treatment with supplement or placebo for approximately 26 weeks after completion of the exercise training. During this time subjects will not be allowed to perform resistance exercise.

Other names: Detraining Period

Nutritional Supplement (Muscle Armor)

Dietary Supplement

Subjects in the supplement group will consume orange-flavored Muscle Armor according to the manufacturer's directions: one serving (approximately 30g, i.e. one scoop provided with the product by its manufacturer), twice daily mixed with 12 ounces (oz) of water beginning after all baseline assessments are performed including assessment of the response to acute exercise and continuing until the end of study participation.

Placebo (Kool-Aid)

Dietary Supplement

Subjects in the placebo group will consume orange-flavored Kool-Aid (Kraft Foods) according to the manufacturer's directions: one serving (approximately 13g, i.e. one scoop provided with the product by the pharmacy), twice daily mixed with 12 ounces (oz) of water beginning after all baseline assessments are performed including assessment of the response to acute exercise and continuing until the end of study participation.

Primary outcomes

  1. Change in Plasma Concentration of Antibodies to Pertussis Antigen (1 Week Post-vaccine)

    Time frame: change from baseline at 1 week post-vaccine

    The change in plasma antibody concentration for response to the pertussis antigen within the tetanus, diphtheria, and pertussis (TDAP) vaccination will be measured between baseline and one week post-vaccination.

  2. Change in Plasma Concentration of Antibodies to Pertussis Antigen (2 Weeks Post-vaccine)

    Time frame: change from baseline at 2 weeks post-vaccine

    The change in plasma antibody concentration for response to the pertussis antigen within the tetanus, diphtheria, and pertussis (TDAP) vaccination will be measured between baseline and two weeks post-vaccination.

  3. Change in Plasma Concentration of C-Reactive Protein

    Time frame: change from baseline at 2 weeks of treatment

    Plasma c-reactive protein will be measured before and after two weeks of treatment with supplement or placebo.

  4. Change in the Number of Muscle Macrophages Per Myofiber (Pre- to Post-acute Exercise)

    Time frame: change from baseline at 2 weeks of treatment

    The change in the number of muscle macrophages per myofiber will be calculated for muscle collected before and 72 hours after a single bout of resistance exercise. The changes in macrophage numbers before and after two weeks of treatment with supplement or placebo will be compared.

  5. Change in Muscle Strength After Exercise Training for 12 Weeks

    Time frame: change from baseline at completion of exercise training phase (12 weeks)

    The change in muscle strength after exercise training will be measured as the difference in one-repetition maximum capability for knee extension from before and after completion of the exercise training program.

Secondary outcomes

  1. Change in Plasma Concentration of Antibodies to Tetanus Antigen (1 Week Post-vaccine)

    Time frame: change from baseline at 1 week post-vaccine

    The change in plasma antibody concentration for response to the tetanus antigen within the tetanus, diphtheria, and pertussis (TDAP) vaccination will be measured between baseline and one week post-vaccination.

  2. Change in Plasma Concentration of Antibodies to Tetanus Antigen (2 Weeks Post-vaccine)

    Time frame: change from baseline at 2 weeks post-vaccine

    The change in plasma antibody concentration for response to the tetanus antigen within the tetanus, diphtheria, and pertussis (TDAP) vaccination will be measured between baseline and two weeks post-vaccination.

  3. Change in Plasma Concentration of Antibodies to Diptheria Antigen (1 Week Post-vaccine)

    Time frame: change from baseline at 1 week post-vaccine

    The change in plasma antibody concentration for response to the diptheria antigen within the tetanus, diphtheria, and pertussis (TDAP) vaccination will be measured between baseline and one week post-vaccination.

  4. Change in Plasma Concentration of Antibodies to Diptheria Antigen (2 Weeks Post-vaccine)

    Time frame: change from baseline at 2 weeks post-vaccine

    The change in plasma antibody concentration for response to the diptheria antigen within the tetanus, diphtheria, and pertussis (TDAP) vaccination will be measured between baseline and two weeks post-vaccination.

  5. Number of Muscle Macrophages Per Myofiber (Resting)

    Time frame: change from baseline at 2 weeks of treatment

    The number of muscle macrophages per myofiber will be counted for resting muscle collected before and after two weeks of treatment with supplement or placebo.

  6. Change in Muscle Size After Exercise Training for 12 Weeks

    Time frame: change from baseline at completion of exercise training phase (12 weeks)

    The change in size of the thigh muscle group after exercise training will be measured as the difference in cross-sectional area based on CT scan before and after completion of the exercise training program.

  7. Change in Muscle Strength at Week 16 of the Post-Training Period

    Time frame: difference between baseline and time point one of de-training follow-up period (week 16)

    The change in muscle strength (one-repetition maximum for knee extension) after completion of the exercise training program will be measured during a follow-up period lacking exercise.

  8. Change in Balance After Exercise Training for 12 Weeks

    Time frame: change from baseline at completion of exercise training (12 weeks)

    The change in balance ability after exercise training will be measured as the difference in Berg Balance Scale (Min 0, Max 56, Higher is Better) score between before and after completion of the exercise training program.

  9. Change in Balance During the Post-Training Period at 26 Weeks of the Post-training Period

    Time frame: difference between time of training completion and time point two of de-training follow-up period (26 weeks)

    The change in balance based on the Berg Balance Scale (Min 0, Max 56, Higher is Better) score will be measured during a follow-up period lacking exercise after completion of the exercise training program.

  10. Change in Balance at Week 16 of the Post-Training Period

    Time frame: difference between time of training completion and time point one of de-training follow-up period (week 16)

    The change in balance based on the Berg Balance Scale (Min 0, Max 56, Higher is Better) score will be measured during a follow-up period lacking exercise after completion of the exercise training program.

  11. Change in Walking Ability After Exercise Training for 12 Weeks

    Time frame: change from baseline at completion of exercise training (12 weeks)

    The change in walking ability after exercise training will be measured using the six minute walk test, i.e. the distance the participant can walk without shortness of breath in six minutes.

  12. Change in Walking Ability at Week 16 of the Post-Training Period

    Time frame: difference between end of training and time point one of de-training follow-up period (week 16)

    The change in walking ability based on the six-minute walk test will be measured during a follow-up period lacking exercise after completion of the exercise training program.

  13. Change in Walking Ability at Week 26 of the Post-Training Period

    Time frame: difference between end of training and time point two of de-training follow-up period (week 26)

    The change in walking ability based on the six-minute walk test will be measured during a follow-up period lacking exercise after completion of the exercise training program.

  14. Change in Gait Speed After Exercise Training for 12 Weeks

    Time frame: change from baseline at completion of exercise training (12 weeks)

    The change in gait speed ability after exercise training will be measured as the difference in habitual walking speed for 10 meters before and after completion of the exercise training program.

  15. Change in Gait Speed at Week 16 of the Post-Training Period

    Time frame: difference between after training and time point one of de-training follow-up period (week 16)

    The change in habitual walking speed over 10 meters will be measured as the difference between values at the end of the training program and time points during a follow-up period lacking exercise.

  16. Change in Gait Speed During at Week 26 of the Post-Training Period

    Time frame: difference between after training and time point two of de-training follow-up period (week 26)

    The change in habitual walking speed over 10 meters will be measured as the difference between values at the end of the training program and time points during a follow-up period lacking exercise.

  17. Change in Muscle Size at Week 26 of the Post-Training Period

    Time frame: difference between baseline and time point two of de-training follow-up period (week 26)

    The change in size of the thigh muscle group during the post-training period will be measured as the difference in cross-sectional area based on CT scan at the end of the training program and at the end of study participation.

  18. Change in Timed Up and Go After Exercise Training for 12 Weeks

    Time frame: change from baseline at completion of exercise training (12 weeks)

    The change in time required to rise from a chair, walk three meters, turn around, walk back to the chair, and sit down will be measured as the difference between before and after completion of the exercise training program.

  19. Change in Timed Up and Go at Week 16 of the Post-Training Period

    Time frame: difference between after training and time point one of de-training follow-up period (week 16)

    The change in time required to rise from a chair, walk three meters, turn around, walk back to the chair, and sit down will be measured as the difference between time points at the end of the training program and during the post-training period.

  20. Change in Timed Up and Go at Week 26 of the Post-Training Period

    Time frame: difference between after training and time point two of de-training follow-up period (week 26)

    The change in time required to rise from a chair, walk three meters, turn around, walk back to the chair, and sit down will be measured as the difference between time points at the end of the training program and during the post-training period.

  21. Percent Change in Resting Muscle Concentration of Interleukin-1 Beta

    Time frame: change from baseline at 2 weeks of treatment

    The muscle concentration of interleukin-1 beta will be measured before and after two weeks of treatment with supplement or placebo.

  22. Change in Muscle Concentration of Interleukin-1 Beta (Pre- to Post-acute Exercise)

    Time frame: change from baseline at 2 weeks of treatment

    The change in the muscle concentration of interleukin-1 beta before and one hour after a single bout of resistance exercise. The changes in macrophage numbers before and after two weeks of treatment with supplement or placebo will be compared.

  23. Change in Resting Muscle Atrophy Gene MURF Expression

    Time frame: percent change from baseline at 2 weeks of treatment

    The change in resting muscle atrophy gene MURF expression will be measured before and after two weeks of treatment with supplement or placebo.

  24. Change in Resting Muscle Atrophy Gene MURF Expression (Post-acute Exercise)

    Time frame: change from baseline at 2 weeks of treatment

    The change in resting muscle atrophy gene MURF expression will be measured before and 72 hours after a single bout of exercise completed before and after two weeks of treatment with supplement or placebo.

  25. Change in Resting Muscle Protein Kinase B

    Time frame: change from baseline at 2 weeks of treatment

    The change in resting muscle Protein Kinase B will be measured before and after two weeks of treatment with supplement or placebo.

  26. Change in Muscle Protein Kinase B (Post-acute Exercise)

    Time frame: change from baseline at 2 weeks of treatment

    The change in muscle Protein Kinase B will be measured before and 72 hours after a single bout of exercise completed before and after two weeks of treatment with supplement or placebo.

  27. Change in Number of Muscle Satellite Cells After Exercise Training for 12 Weeks

    Time frame: change from baseline at completion of exercise training (12 weeks)

    The change in the satellite cell content of muscle will be measured as the difference in the number of satellite cells in muscle before and after completion of the exercise training program.

  28. Change in Number of Myonuclei After Exercise Training for 12 Weeks

    Time frame: change from baseline at completion of exercise training (12 weeks)

    The change in the myonuclear content of muscle will be measured as the difference in the number of myonuclei in muscle before and after completion of the exercise training program.

  29. Change in Muscle Fiber Size After Exercise Training for 12 Weeks

    Time frame: change from baseline at completion of exercise training (12 weeks)

    The change in the muscle fiber size will be measured as the difference in fiber size before and after completion of the exercise training program.

Other outcomes

  1. Plasma Concentration of Aspartate Aminotransferase After Product Consumption for 15 Weeks

    Time frame: at completion of the exercise training program (15 weeks)

    Plasma aspartate aminotransferase will be measured as a safety indicator of liver function at baseline, after completion of the exercise training program, and at the end of the study.

  2. Plasma Concentration of Alanine Aminotransferase After Product Consumption for 15 Weeks

    Time frame: completion of the exercise training program (15 weeks)

    Plasma Alanine Aminotransferase will be measured as a safety indicator of liver function at baseline, after completion of the exercise training program, and at the end of the study.

  3. Ratio of Plasma Concentrations of Blood Urea Nitrogen to Creatinine After Product Consumption for 15 Weeks

    Time frame: completion of the exercise training program (15 weeks)

    Plasma blood urea nitrogen and creatinine will be measured as a safety indicator of kidney function at baseline, after completion of the exercise training program, and at the end of the study.

  4. Plasma Concentration of Aspartate Aminotransferase After 42 Weeks of Product Consumption

    Time frame: end of study (42 weeks)

    Plasma aspartate aminotransferase will be measured as a safety indicator of liver function at baseline, after completion of the exercise training program, and at the end of the study.

  5. Plasma Concentration of Alanine Aminotransferase After 42 Weeks of Product Consumption

    Time frame: end of study (42 weeks)

    Plasma Alanine Aminotransferase will be measured as a safety indicator of liver function at baseline, after completion of the exercise training program, and at the end of the study.

  6. Ratio of Plasma Concentrations of Blood Urea Nitrogen to Creatinine After 42 Weeks of Product Consumption

    Time frame: end of study (42 weeks)

    Plasma blood urea nitrogen and creatinine will be measured as a safety indicator of kidney function at baseline, after completion of the exercise training program, and at the end of the study.

  7. Change in Muscle Strength at Week 26 of the Post-Training Period

    Time frame: difference between baseline and time point two of de-training follow-up period (week 26)

    The change in muscle strength (one-repetition maximum for knee extension) after completion of the exercise training program will be measured during a follow-up period lacking exercise.

  8. Plasma Concentration of Aspartate Aminotransferase

    Time frame: baseline

    Plasma aspartate aminotransferase will be measured as a safety indicator of liver function at baseline, after completion of the exercise training program, and at the end of the study.

  9. Plasma Concentration of Alanine Aminotransferase

    Time frame: baseline

    Plasma Alanine Aminotransferase will be measured as a safety indicator of liver function at baseline, after completion of the exercise training program, and at the end of the study.

  10. Ratio of Plasma Concentrations of Blood Urea Nitrogen to Creatinine

    Time frame: baseline

    Plasma blood urea nitrogen and creatinine will be measured as a safety indicator of kidney function at baseline, after completion of the exercise training program, and at the end of the study.

Sponsors and collaborators

Lead sponsor

VA Office of Research and Development

Fed

Collaborators

  • University of Arkansas

Registry information

Acronym: TDAP2

Important dates

Study start
2014
Primary completion
2018
Study completion
2019
First posted
Oct 10, 2014
Registry last updated
Sep 28, 2021

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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