PT - JOURNAL ARTICLE AU - Meng Zhao AU - Niels Banhos Danneskiold-Samsøe AU - Livia Ulicna AU - Quennie Nguyen AU - Laetitia Voilquin AU - David E. Lee AU - James P. White AU - Zewen Jiang AU - Nickeisha Cuthbert AU - Shrika Paramasivam AU - Ewa Bielczyk-Maczynska AU - Capucine Van Rechem AU - Katrin J. Svensson TI - Phosphoproteomic mapping reveals distinct signaling actions and activation of protein synthesis and muscle hypertrophy by Isthmin-1 AID - 10.1101/2022.05.19.492758 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.05.19.492758 4099 - http://biorxiv.org/content/early/2022/05/25/2022.05.19.492758.short 4100 - http://biorxiv.org/content/early/2022/05/25/2022.05.19.492758.full 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 anti-diabetic circulating protein controls muscle biology.Competing Interest StatementThe authors have declared no competing interest.