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

Author

Listed:
  • Chengyi Sun

    (Cincinnati Children’s Hospital Medical Center)

  • Casey O. Swoboda

    (Cincinnati Children’s Hospital Medical Center
    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
    Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Christoph Lepper

    (The Ohio State University)

  • Douglas P. Millay

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

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.

Suggested Citation

  • Chengyi Sun & Casey O. Swoboda & Fabian Montecino Morales & Cristofer Calvo & Michael J. Petrany & Sreeja Parameswaran & Andrew VonHandorf & Matthew T. Weirauch & Christoph Lepper & Douglas P. Millay, 2024. "Lineage tracing of nuclei in skeletal myofibers uncovers distinct transcripts and interplay between myonuclear populations," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53510-z
    DOI: 10.1038/s41467-024-53510-z
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    References listed on IDEAS

    as
    1. Matthieu Dos Santos & Akansha M. Shah & Yichi Zhang & Svetlana Bezprozvannaya & Kenian Chen & Lin Xu & Weichun Lin & John R. McAnally & Rhonda Bassel-Duby & Ning Liu & Eric N. Olson, 2023. "Opposing gene regulatory programs governing myofiber development and maturation revealed at single nucleus resolution," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
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    3. Minchul Kim & Vedran Franke & Bettina Brandt & Elijah D. Lowenstein & Verena Schöwel & Simone Spuler & Altuna Akalin & Carmen Birchmeier, 2020. "Single-nucleus transcriptomics reveals functional compartmentalization in syncytial skeletal muscle cells," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    4. F. Relaix & M. Bencze & M. J. Borok & A. Vartanian & F. Gattazzo & D. Mademtzoglou & S. Perez-Diaz & A. Prola & P. C. Reyes-Fernandez & A. Rotini & Taglietti, 2021. "Perspectives on skeletal muscle stem cells," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    5. Kenth-Arne Hansson & Einar Eftestøl & Jo C. Bruusgaard & Inga Juvkam & Alyssa W. Cramer & Anders Malthe-Sørenssen & Douglas P. Millay & Kristian Gundersen, 2020. "Myonuclear content regulates cell size with similar scaling properties in mice and humans," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    6. Matthieu Santos & Stéphanie Backer & Benjamin Saintpierre & Brigitte Izac & Muriel Andrieu & Franck Letourneur & Frederic Relaix & Athanassia Sotiropoulos & Pascal Maire, 2020. "Single-nucleus RNA-seq and FISH identify coordinated transcriptional activity in mammalian myofibers," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    7. Michael J. Petrany & Casey O. Swoboda & Chengyi Sun & Kashish Chetal & Xiaoting Chen & Matthew T. Weirauch & Nathan Salomonis & Douglas P. Millay, 2020. "Single-nucleus RNA-seq identifies transcriptional heterogeneity in multinucleated skeletal myofibers," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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