Lineage tracing of nuclei in skeletal myofibers uncovers distinct transcripts and interplay between myonuclear populations

Chengyi Sun, Casey O. Swoboda, Fabian Montecino Morales, Cristofer Calvo, Michael J. Petrany, Sreeja Parameswaran, Andrew VonHandorf, Matthew T. Weirauch, Christoph Lepper and Douglas P. Millay ()
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Chengyi Sun: Cincinnati Children’s Hospital Medical Center
Casey O. Swoboda: Cincinnati Children’s Hospital Medical Center
Fabian Montecino Morales: Cincinnati Children’s Hospital Medical Center
Cristofer Calvo: Cincinnati Children’s Hospital Medical Center
Michael J. Petrany: Cincinnati Children’s Hospital Medical Center
Sreeja Parameswaran: Cincinnati Children’s Hospital Medical Center
Andrew VonHandorf: Cincinnati Children’s Hospital Medical Center
Matthew T. Weirauch: Cincinnati Children’s Hospital Medical Center
Christoph Lepper: The Ohio State University
Douglas P. Millay: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Multinucleated skeletal muscle cells need to acquire additional nuclei through fusion with activated skeletal muscle stem cells when responding to both developmental and adaptive growth stimuli. A fundamental question in skeletal muscle biology has been the reason underlying this need for new nuclei in cells that already harbor hundreds of nuclei. Here we utilize nuclear RNA-sequencing approaches and develop a lineage tracing strategy capable of defining the transcriptional state of recently fused nuclei and distinguishing this state from that of pre-existing nuclei. Our findings reveal the presence of conserved markers of newly fused nuclei both during development and after a hypertrophic stimulus in the adult. However, newly fused nuclei also exhibit divergent gene expression that is determined by the myogenic environment to which they fuse. Moreover, accrual of new nuclei through fusion is required for nuclei already resident in adult myofibers to mount a normal transcriptional response to a load-inducing stimulus. We propose a model of mutual regulation in the control of skeletal muscle development and adaptations, where newly fused and pre-existing myonuclear populations influence each other to maintain optimal functional growth.

Date: 2024
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DOI: 10.1038/s41467-024-53510-z

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