Study shoots down hopes that metformin might help strength training seniors build more muscle

A new clinical trial dispels the hypothesis that the diabetes drug metformin could help exercising seniors gain more muscle mass. The double-blind trial, conducted at the University of Alabama at Birmingham and the University of Kentucky, found that older adults who took metformin while performing rigorous resistance exercise training had smaller gains in muscle mass than did the placebo group. The results of the trial were published in Aging Cell on Sept. 26.

“In older adults, age 65 and up, who have lost significant muscle mass and function over prior decades, we thought metformin might combat muscle inflammation and thereby boost the muscle regrowth response to resistance training,” said Marcas Bamman, Ph.D., professor in the UAB Department of Cell, Developmental and Integrative Biology and director of the UAB Center for Exercise Medicine. “Instead, metformin impaired the adaptations such that the placebo group experienced greater increases in muscle mass and muscle quality than did the metformin group.”

Bamman says it is well-established that progressive resistance training can help older adults retain or build muscle mass. Those gains are variable among individuals, however; and inflammation in the muscle may contribute. Metformin has anti-inflammatory properties and was a logical candidate to study. The UAB and UK researchers, responding to a request for proposals from the National Institutes of Health, looked at metformin as a means of supplementing resistance training.

The investigators randomized 109 healthy volunteers at UAB and UK with an average age of 69.  Roughly half took 1700 mg of metformin per day, while the other half took placebo pills identical in appearance. Following baseline testing, both groups completed 14 weeks of resistance training. Before and after the exercise period, both groups underwent thigh CT scans, DXA measurement, strength testing and a muscle biopsy.

“DXA and CT scans showed that the placebo group had greater gains in lean muscle mass and thigh muscle mass,” said Charlotte Peterson, Ph.D., professor in the UK College of Health Sciences and director of the Center for Muscle Biology. “CT scans and analysis of the biopsy also allowed us to determine that the quality of the muscle improved in the control group over the metformin group.”

The research team originally hypothesized that metformin would improve exercise response by targeting macrophages, immune cells present in muscle.

“The premise was that metformin would alter macrophage metabolism, converting them from an inflammatory to a reparative phenotype through activation of a kinase called AMPK,” said Philip Kern, M.D., director of the UK Center for Clinical and Translational Sciences. “This should then enhance the effect of resistance training in older adults.”

“Although metformin activated AMPK, the increase in reparative macrophages with training was comparable between groups. However, AMPK is also known to inhibit another kinase in muscle fibers, mTORC1,” Peterson said. “mTORC1 is a key regulator of muscle growth. Metformin’s inhibition of that pathway is likely the reason that the metformin group did not see the same gains in muscle mass as the control group.”

“Progressive resistance exercise training remains the one intervention that we know will boost muscle gain in seniors; however, we also know that not all people respond to exercise to the same degree,” Bamman said. “For those low responders to resistance training, it might be beneficial to have an adjunct that would boost their response and enhance their gains. But clearly metformin isn’t the one.”

The study was funded by National Institute on Aging, Grant/Award Number R01AG046920 and National Center for Advancing Translational Sciences, Grant/Award Numbers UL1TR001998 and UL1TR003096. The Centers for Clinical and Translational Sciences at UAB and UK were instrumental in conducting the study.

Additional authors from the University of Kentucky are R. Grace Walton, Cory M. Dungan, Douglas E. Long, Kate Kosmac and Bailey D. Peck, Center for Muscle Biology; Heather M. Bush, Department of Biostatics; and Alejandro G. Villasante Tezanos, Department of Statistics.

Additional authors from UAB are S. Craig Tuggle, Center for Exercise Medicine; Gerald McGwin, Ph.D., Department of Epidemiology; Samuel T. Windham, M.D., Department of Surgery; and Fernando Ovalle, M.D., Department of Medicine.

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