The Hippo pathway controls myofibril assembly and muscle fiber growth by regulating sarcomeric gene expression

  1. Aynur Kaya-Çopur  Is a corresponding author
  2. Fabio Marchiano
  3. Marco Y Hein
  4. Daniel Alpern
  5. Julie Russeil
  6. Nuno Miguel Luis
  7. Matthias Mann
  8. Bart Deplancke
  9. Bianca H Habermann
  10. Frank Schnorrer  Is a corresponding author
  1. Aix Marseille University, CNRS, IDBM, France
  2. Max Planck Institute of Biochemistry, Germany
  3. École Polytechnique Fédérale de Lausanne (EPFL), Switzerland
  4. Aix Marseille University, CNRS, France

Abstract

Skeletal muscles are composed of gigantic cells called muscle fibers, packed with force-producing myofibrils. During development the size of individual muscle fibers must dramatically enlarge to match with skeletal growth. How muscle growth is coordinated with growth of the contractile apparatus is not understood. Here, we use the large Drosophila flight muscles to mechanistically decipher how muscle fiber growth is controlled. We find that regulated activity of core members of the Hippo pathway is required to support flight muscle growth. Interestingly, we identify Dlg5 and Slmap as regulators of the STRIPAK phosphatase, which negatively regulates Hippo to enable post-mitotic muscle growth. Mechanistically, we show that the Hippo pathway controls timing and levels of sarcomeric gene expression during development and thus regulates the key components that physically mediate muscle growth. Since Dlg5, STRIPAK and the Hippo pathway are conserved a similar mechanism may contribute to muscle or cardiomyocyte growth in humans.

Data availability

Sequencing data have been deposited in GEO under accession code GSE158957

The following data sets were generated

Article and author information

Author details

  1. Aynur Kaya-Çopur

    Muscle Dynamics, Aix Marseille University, CNRS, IDBM, Marseille, France
    For correspondence
    aynur.KAYA-COPUR@univ-amu.fr
    Competing interests
    The authors declare that no competing interests exist.
  2. Fabio Marchiano

    Computational Biology, Aix Marseille University, CNRS, IDBM, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Marco Y Hein

    Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9490-2261
  4. Daniel Alpern

    Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Julie Russeil

    Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Nuno Miguel Luis

    Institut de Biologie du Développement de Marseille, Aix Marseille University, CNRS, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5438-9638
  7. Matthias Mann

    Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1292-4799
  8. Bart Deplancke

    School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9935-843X
  9. Bianca H Habermann

    Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2457-7504
  10. Frank Schnorrer

    Muscle Dynamics, Aix Marseille University, CNRS, IDBM, Marseille, France
    For correspondence
    frank.schnorrer@univ-amu.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9518-7263

Funding

European Research Council ERC (FP/2007-2013)

  • Frank Schnorrer

Bettencourt Foundation

  • Frank Schnorrer

Turing Center for Living Systems

  • Frank Schnorrer

Max Planck Society

  • Frank Schnorrer

Centre National de la Recherche Scientifique

  • Frank Schnorrer

Aix-Marseille Université (ANR-11-IDEX-0001-02)

  • Frank Schnorrer

Agence Nationale de la Recherche (ANR-ACHN MUSCLE-FORCES)

  • Frank Schnorrer

Agence Nationale de la Recherche (ANR-18-CE45-0016-01)

  • Bianca H Habermann

Human Frontier Science Program (RGP0052/2018)

  • Frank Schnorrer

Agence Nationale de la Recherche (ANR-10-INBS-04-01)

  • Frank Schnorrer

Humboldt Foundation

  • Aynur Kaya-Çopur

EMBO

  • Aynur Kaya-Çopur

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2021, Kaya-Çopur et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,255
    views
  • 491
    downloads
  • 41
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Aynur Kaya-Çopur
  2. Fabio Marchiano
  3. Marco Y Hein
  4. Daniel Alpern
  5. Julie Russeil
  6. Nuno Miguel Luis
  7. Matthias Mann
  8. Bart Deplancke
  9. Bianca H Habermann
  10. Frank Schnorrer
(2021)
The Hippo pathway controls myofibril assembly and muscle fiber growth by regulating sarcomeric gene expression
eLife 10:e63726.
https://doi.org/10.7554/eLife.63726

Share this article

https://doi.org/10.7554/eLife.63726

Further reading

    1. Cell Biology
    2. Developmental Biology
    Pavan K Nayak, Arul Subramanian, Thomas F Schilling
    Research Article Updated

    Mechanical forces play a critical role in tendon development and function, influencing cell behavior through mechanotransduction signaling pathways and subsequent extracellular matrix (ECM) remodeling. Here, we investigate the molecular mechanisms by which tenocytes in developing zebrafish embryos respond to muscle contraction forces during the onset of swimming and cranial muscle activity. Using genome-wide bulk RNA sequencing of FAC-sorted tenocytes we identify novel tenocyte markers and genes involved in tendon mechanotransduction. Embryonic tendons show dramatic changes in expression of matrix remodeling associated 5b (mxra5b), matrilin 1 (matn1), and the transcription factor kruppel-like factor 2a (klf2a), as muscles start to contract. Using embryos paralyzed either by loss of muscle contractility or neuromuscular stimulation we confirm that muscle contractile forces influence the spatial and temporal expression patterns of all three genes. Quantification of these gene expression changes across tenocytes at multiple tendon entheses and myotendinous junctions reveals that their responses depend on force intensity, duration, and tissue stiffness. These force-dependent feedback mechanisms in tendons, particularly in the ECM, have important implications for improved treatments of tendon injuries and atrophy.

    1. Developmental Biology
    Cora Demler, John C Lawlor ... Natasza A Kurpios
    Research Article

    Correct intestinal morphogenesis depends on the early embryonic process of gut rotation, an evolutionarily conserved program in which a straight gut tube elongates and forms into its first loops. However, the gut tube requires guidance to loop in a reproducible manner. The dorsal mesentery (DM) connects the gut tube to the body and directs the lengthening gut into stereotypical loops via left-right (LR) asymmetric cellular and extracellular behavior. The LR asymmetry of the DM also governs blood and lymphatic vessel formation for the digestive tract, which is essential for prenatal organ development and postnatal vital functions including nutrient absorption. Although the genetic LR asymmetry of the DM has been extensively studied, a divider between the left and right DM has yet to be identified. Setting up LR asymmetry for the entire body requires a Lefty1+ midline barrier to separate the two sides of the embryo, without it, embryos have lethal or congenital LR patterning defects. Individual organs including the brain, heart, and gut also have LR asymmetry, and while the consequences of left and right signals mixing are severe or even lethal, organ-specific mechanisms for separating these signals remain poorly understood. Here, we uncover a midline structure composed of a transient double basement membrane, which separates the left and right halves of the embryonic chick DM during the establishment of intestinal and vascular asymmetries. Unlike other basement membranes of the DM, the midline is resistant to disruption by intercalation of Netrin4 (Ntn4). We propose that this atypical midline forms the boundary between left and right sides and functions as a barrier necessary to establish and protect organ asymmetry.