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bioRxiv · 10.1101/2024.08.11.606848

Network-based modelling reveals cell-type enriched patterns of non-coding RNA regulation during human skeletal muscle remodelling

Mcleod, J. C.·Lim, C.·Stokes, T.·Sharif, J.-A.·Zeynalli, V.·Wiens, L.·D'Souza, A. C.·Colenso-Semple, L.·McKendry, J.·Morton, R. W.·Mitchell, C. J.·Oikawa, S. Y.·Wahlestedt, C.·Chapple, P.·McGlory, C.·Timmons, J. A.·Phillips, S. M.
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Abstract

A 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 growth in 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, including CYTOR - which was leukocyte-associated (FDR = 4.9 x10-7). Novel hypertrophy-linked ncRNAs included PPP1CB-DT (myofibril assembly genes, FDR = 8.15 x 10-8), and EEF1A1P24 and TMSB4XP8 (vascular remodelling and angiogenesis genes, FDR = 2.77 x 10-5). We also discovered that hypertrophy lncRNA MYREM shows a specific myonuclear expression pattern in 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.

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Mcleod, J. C., Lim, C., Stokes, T., Sharif, J.-A., Zeynalli, V., Wiens, L., D'Souza, A. C., Colenso-Semple, L., McKendry, J., Morton, R. W., Mitchell, C. J., Oikawa, S. Y., Wahlestedt, C., Chapple, P., McGlory, C., Timmons, J. A., Phillips, S. M.. 2024-08-11. Network-based modelling reveals cell-type enriched patterns of non-coding RNA regulation during human skeletal muscle remodelling. https://doi.org/10.1101/2024.08.11.606848

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