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

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).