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

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

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.

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.

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).