Expression profiling by high throughput sequencing
Summary
Evidence from clinical trials and observational studies suggests that both progressive resistance 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 blunted 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.
Overall design
The Metformin to Augment Strength Training Effective Response in Seniors (MASTERS) Trial (ClinicalTrials.gov identifier: NCT02308228) is a randomized, controlled, double blind trial comparing the effects of metformin versus placebo during a 14-week progressive resistance training (PRT) intervention in healthy men and women ≥ 65 years of age. Participants were recruited at University of Kentucky and University of Alabama at Birmingham, UAB. The detailed study design and participant characteristics have been published previously (PMID: 28441958 and PMID: 31557380). Total RNA was isolated from baseline muscle biopsies in 37 plaPRT and 28 metPRT participants and from 16-week post-training muscle biopsies from 26 plaPRT and 24 metPRT participants. Of these, 24 plaPRT and 23 metPRT participants had biopsies at both timepoints. Additionally, total RNA was isolated from muscle biopsies in 21 young healthy donors. RNA content, integrity and purity were determined with a Nanodrop 2000 spectrophotometer and the 2100 Bioanalyzer. A minimum RNA Integrity Number (RIN) of 6.5 was set for all samples.
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