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Priority Research Paper|Volume 12, Issue 20|pp 19852—19866

Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults

Ameya S. Kulkarni1,2, Bailey D. Peck3, R. Grace Walton3, Philip A. Kern4, Jessica C. Mar5, Samuel T. Windham6,7, Marcas M. Bamman6,8,9, Nir Barzilai1,2, Charlotte A. Peterson3
  • 1Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA
  • 2Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
  • 3Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY 40504, USA
  • 4Department of Internal Medicine, Division of Endocrinology, and the Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY 40504, USA
  • 5Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland, Australia
  • 6Center for Exercise Medicine, University of Alabama, Birmingham, AL 35233, USA
  • 7Department of Surgery, School of Medicine, University of Alabama at Birmingham, AL 35233, USA
  • 8Department of Cell, Development and Integrative Biology, School of Medicine, University of Alabama at Birmingham, AL 35233, USA
  • 9Geriatric Research, Education, and Clinical Center, Birmingham VA Medical Center, Birmingham, AL 35233, USA
* Equal contribution
Received: July 6, 2020Accepted: September 17, 2020Published: October 18, 2020
https://doi.org/10.18632/aging.104096

Copyright: © 2020 Kulkarni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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.