Metformin to Augment Strength Training Effective Response in Seniors (MASTERS)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Novel Actions of Metformin to Augment Resistance Training Adaptations in Older Adults

Conditions
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Aging

Intervention / Treatment
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* Behavioral: Progressive Resistance Training
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 65 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>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. | Behavioral: Progressive Resistance Training<br>* 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.<br>* Other names: Strength Training;Drug: Metformin<br>* Participants will be randomized to receive metformin in conjunction with their strength training program.<br>* Other names: Glucophage XR;|
| Placebo Comparator: Placebo, Sugar Pill<br>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. | Behavioral: Progressive Resistance Training<br>* 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.<br>* Other names: Strength Training;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metformin, Aging, Hypertrophy, Strength, Muscle