Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.76649
Keywords
muscle; sarcomere; self-organisation; mechanical tension; human induced pluripotent stem cells; myofibril; Human
Categories
Funding
- Human Frontier Science Program [RGP0052/2018]
- Centre National de la Recherche Scientifique
- European Research Council [ERC-2019-SyG 856118]
- Aix-Marseille Universite [ANR-11-IDEX-0001-02]
- Agence Nationale de la Recherche
- Agence Nationale de la Recherche [ANR-18-CE45-0016-01, ANR-10-INBS-04-01, ANR-16-CONV-0001]
- Turing Centre for Living Systems [ANR-16-CONV-0001]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [F31HD100033]
- la Caixa Foundation [LCF/BQ/AA18/11680032]
- Agence Nationale de la Recherche (ANR) [ANR-18-CE45-0016] Funding Source: Agence Nationale de la Recherche (ANR)
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This study investigates the mechanisms of human muscle morphogenesis using an in vitro system with induced pluripotent stem cell-derived human myogenic precursors. The researchers found that mechanical tension plays a key role in coordinating the multi-scale self-organisation of muscle morphogenesis, including sarcomeric components and differentiating myofibers.
Human muscle is a hierarchically organised tissue with its contractile cells called myofibers packed into large myofiber bundles. Each myofiber contains periodic myofibrils built by hundreds of contractile sarcomeres that generate large mechanical forces. To better understand the mechanisms that coordinate human muscle morphogenesis from tissue to molecular scales, we adopted a simple in vitro system using induced pluripotent stem cell-derived human myogenic precursors. When grown on an unrestricted two-dimensional substrate, developing myofibers spontaneously align and self-organise into higher-order myofiber bundles, which grow and consolidate to stable sizes. Following a transcriptional boost of sarcomeric components, myofibrils assemble into chains of periodic sarcomeres that emerge across the entire myofiber. More efficient myofiber bundling accelerates the speed of sarcomerogenesis suggesting that tension generated by bundling promotes sarcomerogenesis. We tested this hypothesis by directly probing tension and found that tension build-up precedes sarcomere assembly and increases within each assembling myofibril. Furthermore, we found that myofiber ends stably attach to other myofibers using integrin-based attachments and thus myofiber bundling coincides with stable myofiber bundle attachment in vitro. A failure in stable myofiber attachment results in a collapse of the myofibrils. Overall, our results strongly suggest that mechanical tension across sarcomeric components as well as between differentiating myofibers is key to coordinate the multi-scale self-organisation of muscle morphogenesis.
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