Aging
Conditions
Keywords
Aging, Hypertrophy, Metformin, Strength, Muscle
Brief summary
The purpose of this study is to determine whether a commonly prescribed drug, metformin, can enhance the benefits seen during resistance exercise such as increased muscle mass and strength.
Detailed description
Muscle mass and strength are critical determinants not only of a person's quality of life and functional independence, but also metabolic health, as muscle is the organ primarily responsible for insulin-mediated glucose uptake. The elderly suffer obligatory losses of muscle mass and strength, exacerbated by illness and physical inactivity. Progressive resistance exercise training (PRT) is the most effective intervention identified to improve muscular strength, and combat the muscle atrophy of aging (sarcopenia); however, overall the muscle response to PRT is blunted in the elderly and variability of response increased, with some individuals actually losing muscle mass. The Bamman and Peterson labs have independently been studying the molecular and cellular mechanisms underlying the non-responder phenotype, with the goal of identifying novel intervention strategies to promote mass and strength gains to improve function. We hypothesize that the abundance of anti-inflammatory, alternatively activated M2 macrophages in muscle predicts response to PRT in the elderly; those with the highest number of M2 macrophages and lowest inflammatory gene expression prior to the start of training gained the most mass. Further, we determined that metformin treatment increased M2 macrophage abundance, and decreased inflammatory cytokine gene expression. These provocative findings have led us to our central hypothesis that adjuvant metformin may improve the responses to PRT in the elderly by altering the muscle tissue inflammatory environment, thereby enhancing mechanisms that drive PRT-induced myofiber hypertrophy.
Interventions
BEHAVIORALProgressive Resistance Training
Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally.
DRUGMetformin
Participants will be randomized to receive metformin in conjunction with their strength training program.
Sponsors
University of Alabama at Birmingham
Philip Kern
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* ≥65 years of age. * Independently mobile with a SPPB score 3-12. * Access to transportation. * Capable of providing informed consent (cognitively intact).
Exclusion criteria
* Obesity (BMI\>30) * Serum creatinine \>1.4 because of risk of lactic acidosis with metformin. * History of regular resistance training within the past year. * History (or ECG evidence) of previous myocardial infarction, history of congestive heart failure. * Current angina pectoris or symptoms of myocardial ischemia or congestive heart failure. * Chronic aspirin or NSAID use (unless it can be safely stopped prior to the biopsies), and any other use of an anticoagulant (e.g., Coumadin) or history of bleeding. * History of alcoholism or liver disease. * History of hypo- or hyper-coagulation disorders including subjects taking Coumadin. * Any end-stage disease and/or a life expectancy less than one year. * Neurological, musculoskeletal, or other disorder that would preclude them from completing resistance training and all performance tests. * Uncontrolled hypertension. * Diabetes mellitus as demonstrated with- HgbA1C\>6.5, or fasting glu\>126 mg/dl. * Any other medical condition that would interfere with testing or increase one's risk of complications during exercise, as judged by the study physicians. * Any other condition or events considered exclusionary by the PI and/or physician, such as non-compliance. * Lidocaine allergy (1% lidocaine is the local anesthetic used during the muscle biopsy procedure).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Type 2 Myofiber Cross Sectional Area | 16 weeks | The ability of metformin to improve the hypertrophic response to resistance training will be determined. Muscle biopsies of the vastus lateralis will be used to quantify myofiber cross-sectional area. The percent change in type 2 myofiber size between week 16 and week 0 was used. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Normal Density Muscle Size by Computed Tomography | 16 weeks | The ability of metformin to improve the hypertrophic response at the whole muscle level will be quantified by computed tomography. Percent change in normal density muscle area will be calculated as the difference between week 16 and week 0. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Muscle Strength | Week 4 and week 16 | Determine if metformin treatment augments strength gains in conjunction with progressive resistance training by one repetition maximum assessments. Maximum (1RM) leg extension muscle strength was assessed at week 4 (to account for neurological adaptations during the initial stages of the resistance program) and week 16. The percent change from week 4 to week 16 is reported. |
| Percent Change in Total Body Lean Mass by DXA | 16 weeks | To determine if metformin improves changes in body composition associated with progressive resistance training. Percent change in total body lean mass in kg was calculated as the difference between week 16 and week 0 from a total body DXA scan. |
| Insulin Sensitivity | 16 weeks | A standard OGTT will be used to determine insulin sensitivity using the Matsuda Index. |
Countries
United States
Participant flow
Recruitment details
Number of individuals consented and further screened for eligibility = 144 Number of participants randomized to drug/placebo = 109 Number of participants completing exercise intervention with drug/placebo use = 94
Pre-assignment details
Participants may have been excluded prior to randomization to study drug for the following reasons: 1. Screen fail (OGTT, ECG, Blood results) 2. Withdrawals (changed mind, lost to follow up, spouse screen fail)
Participants by arm
| Arm | Count |
|---|---|
| Metformin Participants will be randomized to receive Metformin (1700 mg/day) for a period of 16 weeks; 2 weeks of Metformin only followed by 14 weeks of continued Metformin use in combination with progressive resistance training.
Progressive Resistance Training: Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally.
Metformin: Participants will be randomized to receive metformin in conjunction with their strength training program. | 54 |
| Placebo, Sugar Pill Participants will be randomized to receive placebo sugar pills (1700 mg/day) for a period of 16 weeks; 2 weeks of placebo only followed by 14 weeks of continued placebo use in combination with progressive resistance training. Placebos will be almost identical to the Metformin medication.
Progressive Resistance Training: Participants will complete 14 weeks (42 sessions, 3x/week) of progressive resistance training which will consist of 8 constant load movements to train all major muscle groups bilaterally. | 55 |
| Total | 109 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 4 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Metformin | Total | Placebo, Sugar Pill |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 53 Participants | 106 Participants | 53 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 3 Participants | 2 Participants |
| Age, Continuous | 69.4 years | 69.4 years | 69.3 years |
| BMI | 26.9 kg/m^2 STANDARD_DEVIATION 3.1 | 26.3 kg/m^2 STANDARD_DEVIATION 3.1 | 25.7 kg/m^2 STANDARD_DEVIATION 3.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 94 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Physical Activity Survey for the Elderly (PASE) | 155.5 Scores on a Scale | 159.3 Scores on a Scale | 165.7 Scores on a Scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 45 Participants | 92 Participants | 47 Participants |
| Region of Enrollment United States | 54 participants | 109 participants | 55 participants |
| Sex: Female, Male Female | 22 Participants | 51 Participants | 29 Participants |
| Sex: Female, Male Male | 24 Participants | 43 Participants | 19 Participants |
| Short Form-36 Mental Component (SF-36) | 56.7 Scores on a Scale | 56.6 Scores on a Scale | 56.5 Scores on a Scale |
| Short Form-36 Physical Component (SF-36) | 54.7 Scores on a Scale | 55.0 Scores on a Scale | 55.2 Scores on a Scale |
| Short Physical Performance Battery (SPPB) | 11 Scores on a Scale | 11 Scores on a Scale | 11 Scores on a Scale |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 55 |
| other Total, other adverse events | 17 / 54 | 6 / 55 |
| serious Total, serious adverse events | 0 / 54 | 0 / 55 |
Outcome results
Primary
Percent Change in Type 2 Myofiber Cross Sectional Area
The ability of metformin to improve the hypertrophic response to resistance training will be determined. Muscle biopsies of the vastus lateralis will be used to quantify myofiber cross-sectional area. The percent change in type 2 myofiber size between week 16 and week 0 was used.
Time frame: 16 weeks
Population: The largest, highest quality pairs of baseline and week 16 mounts were used for quantification of immunohistochemistry (N=30/group)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Percent Change in Type 2 Myofiber Cross Sectional Area | 18.5 Percent change | Standard Deviation 31.5 |
| Placebo, Sugar Pill | Percent Change in Type 2 Myofiber Cross Sectional Area | 14.5 Percent change | Standard Deviation 29.7 |
Secondary
Percent Change in Normal Density Muscle Size by Computed Tomography
The ability of metformin to improve the hypertrophic response at the whole muscle level will be quantified by computed tomography. Percent change in normal density muscle area will be calculated as the difference between week 16 and week 0.
Time frame: 16 weeks
Population: Missing data points include those who, based on femur area, CT positioning at post measure was incorrect = 16. In addition, 1 subject was excluded from analysis as CT data indicated 45% loss of thigh muscle area, which was not consistent with other data for this subject.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Percent Change in Normal Density Muscle Size by Computed Tomography | 4.2 Percent change | Standard Deviation 9.1 |
| Placebo, Sugar Pill | Percent Change in Normal Density Muscle Size by Computed Tomography | 10.5 Percent change | Standard Deviation 7 |
Other Pre-specified
Insulin Sensitivity
A standard OGTT will be used to determine insulin sensitivity using the Matsuda Index.
Time frame: 16 weeks
Other Pre-specified
Percent Change in Muscle Strength
Determine if metformin treatment augments strength gains in conjunction with progressive resistance training by one repetition maximum assessments. Maximum (1RM) leg extension muscle strength was assessed at week 4 (to account for neurological adaptations during the initial stages of the resistance program) and week 16. The percent change from week 4 to week 16 is reported.
Time frame: Week 4 and week 16
Population: Some participants were not able to complete the procedure on the day of testing, injured etc
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Percent Change in Muscle Strength | 15.3 Percent change | Standard Deviation 18.5 |
| Placebo, Sugar Pill | Percent Change in Muscle Strength | 23.1 Percent change | Standard Deviation 18.9 |
Other Pre-specified
Percent Change in Total Body Lean Mass by DXA
To determine if metformin improves changes in body composition associated with progressive resistance training. Percent change in total body lean mass in kg was calculated as the difference between week 16 and week 0 from a total body DXA scan.
Time frame: 16 weeks
Population: Analysis of lean muscle mass for those who completed the interventions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Percent Change in Total Body Lean Mass by DXA | 0.41 Percent change | Standard Deviation 2.25 |
| Placebo, Sugar Pill | Percent Change in Total Body Lean Mass by DXA | 1.95 Percent change | Standard Deviation 2.69 |