TY - JOUR TI - Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1 AU - Zhao, Meng AU - Banhos Danneskiold-Samsøe, Niels AU - Ulicna, Livia AU - Nguyen, Quennie AU - Voilquin, Laetitia AU - Lee, David E AU - White, James P AU - Jiang, Zewen AU - Cuthbert, Nickeisha AU - Paramasivam, Shrika AU - Bielczyk-Maczynska, Ewa AU - Van Rechem, Capucine AU - Svensson, Katrin J A2 - Cardozo, Christopher A2 - Zaidi, Mone A2 - Cardozo, Christopher A2 - Graham, Zachary VL - 11 PY - 2022 DA - 2022/09/28 SP - e80014 C1 - eLife 2022;11:e80014 DO - 10.7554/eLife.80014 UR - https://doi.org/10.7554/eLife.80014 AB - 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. KW - proteomics KW - signaling KW - muscle JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -