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

Abstract

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.

Advances in research of biological functions of Isthmin-1

“…Skeletal muscle not only controls whole-body energy expenditure, but also serves as a reservoir of protein and is highly sensitive to protein anabolism and catabolism. Recent studies have shown that ISM1 can act directly on skeletal muscle cells to induce protein synthesis via pAKT- pS6 S235/S236 (Zhao et al 2022 ). Skeletal muscle fibers became smaller, protein degradation increased, muscle strength decreased, and muscle atrophy-related FOXO1 target gene levels increased with ISM1 knockdown (Zhao et al 2022 ).…”

“…Recent studies have shown that ISM1 can act directly on skeletal muscle cells to induce protein synthesis via pAKT- pS6 S235/S236 (Zhao et al 2022 ). Skeletal muscle fibers became smaller, protein degradation increased, muscle strength decreased, and muscle atrophy-related FOXO1 target gene levels increased with ISM1 knockdown (Zhao et al 2022 ). This suggests that ISM1 may affect the contractile function of skeletal muscle by regulating its protein synthesis.…”