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Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1.

Publication ,  Journal Article
Zhao, M; Banhos Danneskiold-Samsøe, N; Ulicna, L; Nguyen, Q; Voilquin, L; Lee, DE; White, JP; Jiang, Z; Cuthbert, N; Paramasivam, S ...
Published in: Elife
September 28, 2022

The secreted protein isthmin-1 (Ism1) mitigates diabetes by increasing adipocyte and skeletal muscle glucose uptake by activating the PI3K-Akt pathway. However, while both Ism1 and insulin converge on these common targets, Ism1 has distinct cellular actions suggesting divergence in downstream intracellular signaling pathways. To understand the biological complexity of Ism1 signaling, we performed phosphoproteomic analysis after acute exposure, revealing overlapping and distinct pathways of Ism1 and insulin. We identify a 53% overlap between Ism1 and insulin signaling and Ism1-mediated phosphoproteome-wide alterations in ~450 proteins that are not shared with insulin. Interestingly, we find several unknown phosphorylation sites on proteins related to protein translation, mTOR pathway, and, unexpectedly, muscle function in the Ism1 signaling network. Physiologically, Ism1 ablation in mice results in altered proteostasis, including lower muscle protein levels under fed and fasted conditions, reduced amino acid incorporation into proteins, and reduced phosphorylation of the key protein synthesis effectors Akt and downstream mTORC1 targets. As metabolic disorders such as diabetes are associated with accelerated loss of skeletal muscle protein content, these studies define a non-canonical mechanism by which this antidiabetic circulating protein controls muscle biology.

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Published In

Elife

DOI

EISSN

2050-084X

Publication Date

September 28, 2022

Volume

11

Location

England

Related Subject Headings

  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Protein Biosynthesis
  • Phosphatidylinositol 3-Kinases
  • Muscle, Skeletal
  • Muscle Proteins
  • Mice
  • Mechanistic Target of Rapamycin Complex 1
  • Intercellular Signaling Peptides and Proteins
  • Insulin
 

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Zhao, M., Banhos Danneskiold-Samsøe, N., Ulicna, L., Nguyen, Q., Voilquin, L., Lee, D. E., … Svensson, K. J. (2022). Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1. Elife, 11. https://doi.org/10.7554/eLife.80014
Zhao, Meng, Niels Banhos Danneskiold-Samsøe, Livia Ulicna, Quennie Nguyen, Laetitia Voilquin, David E. Lee, James P. White, et al. “Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1.Elife 11 (September 28, 2022). https://doi.org/10.7554/eLife.80014.
Zhao M, Banhos Danneskiold-Samsøe N, Ulicna L, Nguyen Q, Voilquin L, Lee DE, et al. Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1. Elife. 2022 Sep 28;11.
Zhao, Meng, et al. “Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1.Elife, vol. 11, Sept. 2022. Pubmed, doi:10.7554/eLife.80014.
Zhao M, Banhos Danneskiold-Samsøe N, Ulicna L, Nguyen Q, Voilquin L, Lee DE, White JP, Jiang Z, Cuthbert N, Paramasivam S, Bielczyk-Maczynska E, Van Rechem C, Svensson KJ. Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1. Elife. 2022 Sep 28;11.

Published In

Elife

DOI

EISSN

2050-084X

Publication Date

September 28, 2022

Volume

11

Location

England

Related Subject Headings

  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Protein Biosynthesis
  • Phosphatidylinositol 3-Kinases
  • Muscle, Skeletal
  • Muscle Proteins
  • Mice
  • Mechanistic Target of Rapamycin Complex 1
  • Intercellular Signaling Peptides and Proteins
  • Insulin