Clinical trial NCT02261961: Immune Function and Muscle Adaptations to Resistance Exercise in Older Adults
Official title: Immune Function and Muscle Adaptations to Resistance Exercise in Older Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Sarcopenia
Aging
Immune Function
Keywords: resistance exercise
Juven
exercise training
interleukin-1
insulin-like growth factor
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: University of Arkansas
First posted: 2014-10-10
Enrollment: 59
Sex: ALL
Minimum age (years): 60
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Change in Plasma Concentration of Antibodies to Pertussis Antigen (1 Week Post-vaccine)
timeFrame: change from baseline at 1 week post-vaccine
measure: Change in Plasma Concentration of Antibodies to Pertussis Antigen (2 Weeks Post-vaccine)
timeFrame: change from baseline at 2 weeks post-vaccine
measure: Change in Plasma Concentration of C-Reactive Protein
timeFrame: change from baseline at 2 weeks of treatment
measure: Change in the Number of Muscle Macrophages Per Myofiber (Pre- to Post-acute Exercise)
timeFrame: change from baseline at 2 weeks of treatment
measure: Change in Muscle Strength After Exercise Training for 12 Weeks
timeFrame: change from baseline at completion of exercise training phase (12 weeks)
Secondary outcomes:
measure: Change in Plasma Concentration of Antibodies to Tetanus Antigen (1 Week Post-vaccine)
timeFrame: change from baseline at 1 week post-vaccine
measure: Change in Plasma Concentration of Antibodies to Tetanus Antigen (2 Weeks Post-vaccine)
timeFrame: change from baseline at 2 weeks post-vaccine
measure: Change in Plasma Concentration of Antibodies to Diptheria Antigen (1 Week Post-vaccine)
timeFrame: change from baseline at 1 week post-vaccine
measure: Change in Plasma Concentration of Antibodies to Diptheria Antigen (2 Weeks Post-vaccine)
timeFrame: change from baseline at 2 weeks post-vaccine
measure: Number of Muscle Macrophages Per Myofiber (Resting)
timeFrame: change from baseline at 2 weeks of treatment
measure: Change in Muscle Size After Exercise Training for 12 Weeks
timeFrame: change from baseline at completion of exercise training phase (12 weeks)
measure: Change in Muscle Strength at Week 16 of the Post-Training Period
timeFrame: difference between baseline and time point one of de-training follow-up period (week 16)
measure: Change in Balance After Exercise Training for 12 Weeks
timeFrame: change from baseline at completion of exercise training (12 weeks)
measure: Change in Balance During the Post-Training Period at 26 Weeks of the Post-training Period
timeFrame: difference between time of training completion and time point two of de-training follow-up period (26 weeks)
measure: Change in Balance at Week 16 of the Post-Training Period
timeFrame: difference between time of training completion and time point one of de-training follow-up period (week 16)
measure: Change in Walking Ability After Exercise Training for 12 Weeks
timeFrame: change from baseline at completion of exercise training (12 weeks)
measure: Change in Walking Ability at Week 16 of the Post-Training Period
timeFrame: difference between end of training and time point one of de-training follow-up period (week 16)
measure: Change in Walking Ability at Week 26 of the Post-Training Period
timeFrame: difference between end of training and time point two of de-training follow-up period (week 26)
measure: Change in Gait Speed After Exercise Training for 12 Weeks
timeFrame: change from baseline at completion of exercise training (12 weeks)
measure: Change in Gait Speed at Week 16 of the Post-Training Period
timeFrame: difference between after training and time point one of de-training follow-up period (week 16)
measure: Change in Gait Speed During at Week 26 of the Post-Training Period
timeFrame: difference between after training and time point two of de-training follow-up period (week 26)
measure: Change in Muscle Size at Week 26 of the Post-Training Period
timeFrame: difference between baseline and time point two of de-training follow-up period (week 26)
measure: Change in Timed Up and Go After Exercise Training for 12 Weeks
timeFrame: change from baseline at completion of exercise training (12 weeks)
measure: Change in Timed Up and Go at Week 16 of the Post-Training Period
timeFrame: difference between after training and time point one of de-training follow-up period (week 16)
measure: Change in Timed Up and Go at Week 26 of the Post-Training Period
timeFrame: difference between after training and time point two of de-training follow-up period (week 26)
measure: Percent Change in Resting Muscle Concentration of Interleukin-1 Beta
timeFrame: change from baseline at 2 weeks of treatment
measure: Change in Muscle Concentration of Interleukin-1 Beta (Pre- to Post-acute Exercise)
timeFrame: change from baseline at 2 weeks of treatment
measure: Change in Resting Muscle Atrophy Gene MURF Expression
timeFrame: percent change from baseline at 2 weeks of treatment
measure: Change in Resting Muscle Atrophy Gene MURF Expression (Post-acute Exercise)
timeFrame: change from baseline at 2 weeks of treatment
measure: Change in Resting Muscle Protein Kinase B
timeFrame: change from baseline at 2 weeks of treatment
measure: Change in Muscle Protein Kinase B (Post-acute Exercise)
timeFrame: change from baseline at 2 weeks of treatment
measure: Change in Number of Muscle Satellite Cells After Exercise Training for 12 Weeks
timeFrame: change from baseline at completion of exercise training (12 weeks)
measure: Change in Number of Myonuclei After Exercise Training for 12 Weeks
timeFrame: change from baseline at completion of exercise training (12 weeks)
measure: Change in Muscle Fiber Size After Exercise Training for 12 Weeks
timeFrame: change from baseline at completion of exercise training (12 weeks)
Other outcomes:
measure: Plasma Concentration of Aspartate Aminotransferase After Product Consumption for 15 Weeks
timeFrame: at completion of the exercise training program (15 weeks)
measure: Plasma Concentration of Alanine Aminotransferase After Product Consumption for 15 Weeks
timeFrame: completion of the exercise training program (15 weeks)
measure: Ratio of Plasma Concentrations of Blood Urea Nitrogen to Creatinine After Product Consumption for 15 Weeks
timeFrame: completion of the exercise training program (15 weeks)
measure: Plasma Concentration of Aspartate Aminotransferase After 42 Weeks of Product Consumption
timeFrame: end of study (42 weeks)
measure: Plasma Concentration of Alanine Aminotransferase After 42 Weeks of Product Consumption
timeFrame: end of study (42 weeks)
measure: Ratio of Plasma Concentrations of Blood Urea Nitrogen to Creatinine After 42 Weeks of Product Consumption
timeFrame: end of study (42 weeks)
measure: Change in Muscle Strength at Week 26 of the Post-Training Period
timeFrame: difference between baseline and time point two of de-training follow-up period (week 26)
measure: Plasma Concentration of Aspartate Aminotransferase
timeFrame: baseline
measure: Plasma Concentration of Alanine Aminotransferase
timeFrame: baseline
measure: Ratio of Plasma Concentrations of Blood Urea Nitrogen to Creatinine
timeFrame: baseline
Locations:
city: North Little Rock
country: United States
facility: Central Arkansas Veterans Healthcare System Eugene J. Towbin Healthcare Center, Little Rock, AR
state: Arkansas
Study officials:
affiliation: Central Arkansas Veterans Healthcare System Eugene J. Towbin Healthcare Center, Little Rock, AR
name: Richard A Dennis, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Long DE, Villasante Tezanos AG, Wise JN, Kern PA, Bamman MM, Peterson CA, Dennis RA. A guide for using NIH Image J for single slice cross-sectional area and composition analysis of the thigh from computed tomography. PLoS One. 2019 Feb 7;14(2):e0211629. doi: 10.1371/journal.pone.0211629. eCollection 2019.
citation: Dennis RA, Long DE, Landes RD, Padala KP, Padala PR, Garner KK, Wise JN, Peterson CA, Sullivan DH. Tutorial for using SliceOmatic to calculate thigh area and composition from computed tomography images from older adults. PLoS One. 2018 Oct 2;13(10):e0204529. doi: 10.1371/journal.pone.0204529. eCollection 2018.
citation: Kosmac K, Peck BD, Walton RG, Mula J, Kern PA, Bamman MM, Dennis RA, Jacobs CA, Lattermann C, Johnson DL, Peterson CA. Immunohistochemical Identification of Human Skeletal Muscle Macrophages. Bio Protoc. 2018 Jun 20;8(12):e2883. doi: 10.21769/BioProtoc.2883.
citation: Dennis RA, Ponnappan U, Kodell RL, Garner KK, Parkes CM, Bopp MM, Padala KP, Peterson CA, Padala PR, Sullivan DH. Immune Function and Muscle Adaptations to Resistance exercise in Older Adults: Study Protocol for a Randomized Controlled Trial of a Nutritional Supplement. Trials. 2015 Mar 27;16:121. doi: 10.1186/s13063-015-0631-3.