Molecular Transducers of Human Skeletal Muscle Remodeling under Different Loading States

Stokes, Tanner; Timmons, James A.; Crossland, Hannah; Tripp, Thomas R.; Murphy, Kevin; McGlory, Chris; Mitchell, Cameron J.; Oikawa, Sara Y.; Morton, Robert W.; Phillips, Bethan E.; Baker, Steven K.; Atherton, Phillip J.; Wahlestedt, Claes; Phillips, Stuart M.

Abstract

Loading of skeletal muscle changes the tissue phenotype reflecting altered metabolic and functional demands. In humans, heterogeneous adaptation to loading complicates the identification of the underpinning molecular regulators. A within-person differential loading and analysis strategy reduces heterogeneity for changes in muscle mass by ∼40% and uses a genome-wide transcriptome method that models each mRNA from coding exons and 3′ and 5′ untranslated regions (UTRs). Our strategy detects ∼3–4 times more regulated genes than similarly sized studies, including substantial UTR-selective regulation undetected by other methods. We discover a core of 141 genes correlated to muscle growth, which we validate from newly analyzed independent samples (n = 100). Further validating these identified genes via RNAi in primary muscle cells, we demonstrate that members of the core genes were regulators of protein synthesis. Using proteome-constrained networks and pathway analysis reveals notable relationships with the molecular characteristics of human muscle aging and insulin sensitivity, as well as potential drug therapies.

Citation

Stokes, T., Timmons, J. A., Crossland, H., Tripp, T. R., Murphy, K., McGlory, C., Mitchell, C. J., Oikawa, S. Y., Morton, R. W., Phillips, B. E., Baker, S. K., Atherton, P. J., Wahlestedt, C., & Phillips, S. M. (2020). Molecular Transducers of Human Skeletal Muscle Remodeling under Different Loading States. Cell Reports, 32(5), Article 107980. https://doi.org/10.1016/j.celrep.2020.107980

• Journal Article Type: Article
• Acceptance Date: Jul 9, 2020
• Online Publication Date: Aug 4, 2020
• Publication Date: Aug 4, 2020
• Deposit Date: Jan 11, 2021
• Publicly Available Date: Jan 11, 2021
• Journal: Cell Reports
• Print ISSN: 2211-1247
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 32
• Issue: 5
• Article Number: 107980
• DOI: https://doi.org/10.1016/j.celrep.2020.107980
• Keywords: General Biochemistry, Genetics and Molecular Biology
• Public URL: https://nottingham-repository.worktribe.com/output/5221357
• Publisher URL: https://www.cell.com/cell-reports/fulltext/S2211-1247(20)30965-7
• Additional Information: This article is maintained by: Elsevier; Article Title: Molecular Transducers of Human Skeletal Muscle Remodeling under Different Loading States; Journal Title: Cell Reports; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.celrep.2020.107980; Content Type: article; Copyright: © 2020 The Author(s).