Clinical trial NCT02308228: Metformin to Augment Strength Training Effective Response in Seniors (MASTERS)
Official title: Novel Actions of Metformin to Augment Resistance Training Adaptations in Older Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Aging
Keywords: Aging
Hypertrophy
Metformin
Strength
Muscle
Lead sponsor: University of Kentucky
Sponsor class: OTHER
Collaborators: name: University of Alabama at Birmingham
First posted: 2014-12-04
Enrollment: 109
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Percent Change in Type 2 Myofiber Cross Sectional Area
timeFrame: 16 weeks
Secondary outcomes:
measure: Percent Change in Normal Density Muscle Size by Computed Tomography
timeFrame: 16 weeks
Other outcomes:
measure: Percent Change in Muscle Strength
timeFrame: Week 4 and week 16
measure: Percent Change in Total Body Lean Mass by DXA
timeFrame: 16 weeks
measure: Insulin Sensitivity
timeFrame: 16 weeks
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
Study officials:
affiliation: University of Kentucky
name: Charlotte Peterson, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Kentucky
name: Philip Kern, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Marcas Bamman, Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Long DE, Kosmac K, Dungan CM, Bamman MM, Peterson CA, Kern PA. Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals. Front Physiol. 2022 Apr 14;13:872745. doi: 10.3389/fphys.2022.872745. eCollection 2022.
citation: Long DE, Peck BD, Tuggle SC, Villasante Tezanos AG, Windham ST, Bamman MM, Kern PA, Peterson CA, Walton RG. Associations of muscle lipid content with physical function and resistance training outcomes in older adults: altered responses with metformin. Geroscience. 2021 Apr;43(2):629-644. doi: 10.1007/s11357-020-00315-9. Epub 2021 Jan 18.
citation: Walton RG, Dungan CM, Long DE, Tuggle SC, Kosmac K, Peck BD, Bush HM, Villasante Tezanos AG, McGwin G, Windham ST, Ovalle F, Bamman MM, Kern PA, Peterson CA. Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial. Aging Cell. 2019 Dec;18(6):e13039. doi: 10.1111/acel.13039. Epub 2019 Sep 26.
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: Long DE, Peck BD, Martz JL, Tuggle SC, Bush HM, McGwin G, Kern PA, Bamman MM, Peterson CA. Metformin to Augment Strength Training Effective Response in Seniors (MASTERS): study protocol for a randomized controlled trial. Trials. 2017 Apr 26;18(1):192. doi: 10.1186/s13063-017-1932-5.