Article
Author: Mcleod, Jonathan C. ; McGlory, Chris ; Paul Chapple, J ; Lim, Changhyun ; D’Souza, Alysha C ; Morton, Robert W. ; Colenso-Semple, Lauren ; Wiens, Lucas ; Wahlestedt, Claes ; Stokes, Tanner ; Sharif, Jalil-Ahmad ; Mcleod, Jonathan Cesare ; Phillips, Stuart M ; Phillips, Stuart M. ; Zeynalli, Vagif ; Mcleod, Jonathan C ; Oikawa, Sara Y. ; Timmons, James A ; Oikawa, Sara Y ; Chapple, J Paul ; Timmons, James A. ; Mitchell, Cameron J. ; D'Souza, Alysha C ; McKendry, James ; Chapple, Paul ; Morton, Robert W ; Mitchell, Cameron J
ABSTRACTA majority of human genes produce non-protein-coding RNA (ncRNA), and some have roles in development and disease. Neither ncRNA nor human skeletal muscle is ideally studied using short-read sequencing, so we used a customised RNA pipeline and network modelling to study cell-type specific ncRNA responses during muscle growth at scale. We completed five human resistance-training studies (n=144 subjects), identifying 61% who successfully accrued muscle-mass. We produced 288 transcriptome-wide profiles and found 110 ncRNAs linked to muscle growthin vivo,while a transcriptome-driven network model demonstrated interactions via a number of discrete functional pathways and single-cell types. This analysis included established hypertrophy-related ncRNAs, includingCYTOR– which was leukocyte-associated (FDR = 4.9 x10-7). Novel hypertrophy-linked ncRNAs includedPPP1CB-DT(myofibril assembly genes, FDR = 8.15 x 10-8), andEEF1A1P24andTMSB4XP8(vascular remodelling and angiogenesis genes, FDR = 2.77 x 10-5). We also discovered that hypertrophy lncRNAMYREMshows a specific myonuclear expression patternin vivo. Our multi-layered analyses established that single-cell-associated ncRNA are identifiable from bulk muscle transcriptomic data and that hypertrophy-linked ncRNA genes mediate their association with muscle growth via multiple cell types and a set of interacting pathways.One Sentence SummaryWe used an optimised transcriptomic strategy to identify a set of ncRNA genes regulated during skeletal muscle hypertrophy in one hundred and forty-four people, with network modelling and spatial imaging providing biological context.
