A new study published in Aging has shown that although taking metformin while undergoing resistance training limits muscle growth, it promotes youthful gene expression.
As the researchers of this study point out, previous research shows that taking metformin while undergoing physical resistance training (PRT) restricts the development of hypertrophy . While hypertrophy is not always desirable in cells, muscle hypertrophy is responsible for bodybuilding and general muscle growth. Therefore, taking metformin while attempting to build strength through PRT makes the training less effective.
The researchers show that this antagonistic effect of metformin can be attributed to its effects on the transcriptome: the gene expression profile of cells. Many of the gene expressions that cause PRT to cause muscle hypertrophy and increase strength were blocked by metformin.
PRT has substantial positive effects on the human body beyond muscle building. While it causes some genes responsible for muscle growth to be expressed, it reduces the number of differentially expressed genes in total; these genes may produce non-functional proteins and increase with age. Metformin was shown to enhance this effect, as more genes retained their youthful expression profiles when PRT was combined with metformin. The researchers had originally hypothesized that reduced inflammation was responsible for this effect, but neither PRT nor metformin reduce muscle inflammation.
Metformin was shown to affect several important aging-associated pathways, including senescence and autophagy, a generally beneficial maintenance process in which cells consume their own organelles. Substantial effects on metabolism were observed when metformin was combined with PRT, most notably lipid (fat) metabolism. Older people who took metformin in addition to undergoing resistance training had a more youthful ability to deal with lipids.
Evidence from clinical trials and observational studies suggests that both progressive resistance exercise training (PRT) and metformin delay a variety of age-related morbidities. Previously, we completed a clinical trial testing the effects of 14 weeks of PRT + metformin (metPRT) compared to PRT with placebo (plaPRT) on muscle hypertrophy in older adults. We found that metformin blunted PRT-induced muscle hypertrophic response. To understand potential mechanisms underlying the inhibitory effect of metformin on PRT, we analyzed the muscle transcriptome in 23 metPRT and 24 plaPRT participants. PRT significantly increased expression of genes involved in extracellular matrix remodeling pathways, and downregulated RNA processing pathways in both groups, however, metformin attenuated the number of differentially expressed genes within these pathways compared to plaPRT. Pathway analysis showed that genes unique to metPRT modulated aging-relevant pathways, such as cellular senescence and autophagy. Differentially expressed genes from baseline biopsies in older adults compared to resting muscle from young volunteers were reduced following PRT in plaPRT and were further reduced in metPRT. We suggest that although metformin may blunt pathways induced by PRT to promote muscle hypertrophy, adjunctive metformin during PRT may have beneficial effects on aging-associated pathways in muscle from older adults.
While the researchers do not recommend healthy older adults to take metformin, this gene expression analysis offers a baseline for the development of future treatments that directly affect sarcopenia and other symptoms of aging. Ideally, it would be possible to develop a treatment that preserves the muscle-building effects of PRT while retaining the youthful gene expression effects of metformin.
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 Walton, R. G., Dungan, C. M., Long, D. E., Tuggle, S. C., Kosmac, K., Peck, B. D., … & Ovalle, F. (2019). 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, 18(6), e13039.