Muscle function and homeostasis require cytokine inhibition of AKT activity in Drosophila

  1. Katrin Kierdorf  Is a corresponding author
  2. Fabian Hersperger
  3. Jessica Sharrock
  4. Crystal M Vincent
  5. Pinar Ustaoglu
  6. Jiawen Dou
  7. Attila Gyoergy
  8. Olaf Gross
  9. Daria E Siekhaus
  10. Marc S Dionne  Is a corresponding author
  1. University of Freiburg, Germany
  2. Imperial College London, United Kingdom
  3. Institute of Science and Technology Austria, Austria

Abstract

Unpaired ligands are secreted signals that act via a GP130-like receptor, domeless, to activate JAK/STAT signaling in Drosophila. Like many mammalian cytokines, unpaireds can be activated by infection and other stresses and can promote insulin resistance in target tissues. However, the importance of this effect in non-inflammatory physiology is unknown. Here, we identify a requirement for unpaired-JAK signaling as a metabolic regulator in healthy adult Drosophila muscle. Adult muscles show basal JAK-STAT signaling activity in the absence of any immune challenge. Plasmatocytes (Drosophila macrophages) are an important source of this tonic signal. Loss of the dome receptor on adult muscles significantly reduces lifespan and causes local and systemic metabolic pathology. These pathologies result from hyperactivation of AKT and consequent deregulation of metabolism. Thus, we identify a cytokine signal that must be received in muscle to control AKT activity and metabolic homeostasis.

Data availability

Data has been made available on Zenodo, under the doi 10.5281/zenodo.3608626.

The following data sets were generated

Article and author information

Author details

  1. Katrin Kierdorf

    Institute of Neuropathology, University of Freiburg, Freiburg, Germany
    For correspondence
    katrin.kierdorf@uniklinik-freiburg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9272-4780
  2. Fabian Hersperger

    Institute of Neuropathology, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Jessica Sharrock

    Department of Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Crystal M Vincent

    Department of Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Pinar Ustaoglu

    Department of Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Jiawen Dou

    Department of Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Attila Gyoergy

    Institute of Science and Technology Austria, Klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1819-198X
  8. Olaf Gross

    Institute of Neuropathology, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Daria E Siekhaus

    Institute of Science and Technology Austria, Klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8323-8353
  10. Marc S Dionne

    Department of Life Sciences, Imperial College London, London, United Kingdom
    For correspondence
    m.dionne@imperial.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8283-1750

Funding

Wellcome (Investigator Award 207467/Z/17/Z)

  • Marc S Dionne

Biotechnology and Biological Sciences Research Council (Research Grant BB/P000592/1)

  • Katrin Kierdorf
  • Pinar Ustaoglu
  • Marc S Dionne

Biotechnology and Biological Sciences Research Council (Research Grant BB/L020122/2)

  • Jessica Sharrock
  • Marc S Dionne

Medical Research Council (Research Grant MR/L018802/2)

  • Katrin Kierdorf
  • Marc S Dionne

Deutsche Forschungsgemeinschaft (Research fellowship KI-1876/1)

  • Katrin Kierdorf

Biotechnology and Biological Sciences Research Council (PhD studentship BB/L502169/1)

  • Jessica Sharrock

Deutsche Forschungsgemeinschaft (CIBSS-EXC-2189-Project ID 390939984)

  • Fabian Hersperger

European Commission (ERC starting grant 337689)

  • Olaf Gross

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

Reviewing Editor

  1. K VijayRaghavan, National Centre for Biological Sciences, Tata Institute of Fundamental Research, India

Version history

  1. Received: September 4, 2019
  2. Accepted: January 10, 2020
  3. Accepted Manuscript published: January 16, 2020 (version 1)
  4. Accepted Manuscript updated: January 20, 2020 (version 2)
  5. Version of Record published: February 3, 2020 (version 3)

Copyright

© 2020, Kierdorf 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

  • 2,720
    views
  • 382
    downloads
  • 16
    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. Katrin Kierdorf
  2. Fabian Hersperger
  3. Jessica Sharrock
  4. Crystal M Vincent
  5. Pinar Ustaoglu
  6. Jiawen Dou
  7. Attila Gyoergy
  8. Olaf Gross
  9. Daria E Siekhaus
  10. Marc S Dionne
(2020)
Muscle function and homeostasis require cytokine inhibition of AKT activity in Drosophila
eLife 9:e51595.
https://doi.org/10.7554/eLife.51595

Share this article

https://doi.org/10.7554/eLife.51595

Further reading

    1. Computational and Systems Biology
    2. Developmental Biology
    Gang Xue, Xiaoyi Zhang ... Zhiyuan Li
    Research Article

    Organisms utilize gene regulatory networks (GRN) to make fate decisions, but the regulatory mechanisms of transcription factors (TF) in GRNs are exceedingly intricate. A longstanding question in this field is how these tangled interactions synergistically contribute to decision-making procedures. To comprehensively understand the role of regulatory logic in cell fate decisions, we constructed a logic-incorporated GRN model and examined its behavior under two distinct driving forces (noise-driven and signal-driven). Under the noise-driven mode, we distilled the relationship among fate bias, regulatory logic, and noise profile. Under the signal-driven mode, we bridged regulatory logic and progression-accuracy trade-off, and uncovered distinctive trajectories of reprogramming influenced by logic motifs. In differentiation, we characterized a special logic-dependent priming stage by the solution landscape. Finally, we applied our findings to decipher three biological instances: hematopoiesis, embryogenesis, and trans-differentiation. Orthogonal to the classical analysis of expression profile, we harnessed noise patterns to construct the GRN corresponding to fate transition. Our work presents a generalizable framework for top-down fate-decision studies and a practical approach to the taxonomy of cell fate decisions.

    1. Developmental Biology
    2. Evolutionary Biology
    Zhuqing Wang, Yue Wang ... Wei Yan
    Research Article

    Despite rapid evolution across eutherian mammals, the X-linked MIR-506 family miRNAs are located in a region flanked by two highly conserved protein-coding genes (SLITRK2 and FMR1) on the X chromosome. Intriguingly, these miRNAs are predominantly expressed in the testis, suggesting a potential role in spermatogenesis and male fertility. Here, we report that the X-linked MIR-506 family miRNAs were derived from the MER91C DNA transposons. Selective inactivation of individual miRNAs or clusters caused no discernible defects, but simultaneous ablation of five clusters containing 19 members of the MIR-506 family led to reduced male fertility in mice. Despite normal sperm counts, motility, and morphology, the KO sperm were less competitive than wild-type sperm when subjected to a polyandrous mating scheme. Transcriptomic and bioinformatic analyses revealed that these X-linked MIR-506 family miRNAs, in addition to targeting a set of conserved genes, have more targets that are critical for spermatogenesis and embryonic development during evolution. Our data suggest that the MIR-506 family miRNAs function to enhance sperm competitiveness and reproductive fitness of the male by finetuning gene expression during spermatogenesis.