The final, formatted version of the article will be published soon.
PERSPECTIVE article
Front. Endocrinol.
Sec. Diabetes: Molecular Mechanisms
Volume 15 - 2024 |
doi: 10.3389/fendo.2024.1425426
MG53's non-physiologic interaction with insulin receptor: lack of effect on insulin-stimulated Akt phosphorylation in muscle, heart and liver tissues
Provisionally accepted- 1 University of Virginia, Charlottesville, United States
- 2 Kyoto University, Kyoto, Kyōto, Japan
- 3 Juntendo University, Bunkyō, Tōkyō, Japan
Rationale: MG53's known function in facilitating tissue repair and anti-inflammation has broad applications to regenerative medicine. There is controversy regarding MG53's role in the development of type 2 diabetes mellitus.Objective: This study aims to address this controversy -whether MG53's myokine function contributes to inhibition of insulin signaling in muscle, heart, and liver tissues.We determined the binding affinity of the recombinant human MG53 (rhMG53) to the insulin receptor extracellular domain (IR-ECD) and found low affinity of interaction with Kd (>480 nM). Using cultured C2C12 myotubes and HepG2 cells, we found no effect of rhMG53 on insulin-stimulated Akt phosphorylation (p-Akt). We performed in vivo assay with C57BL/6J mice subjected to insulin stimulation (1 U/kg, intraperitoneal injection) and observed no effect of rhMG53 on insulin-stimulated p-Akt in muscle, heart and liver tissues.Overall, our data suggest that rhMG53 can bind to the IR-ECD, however has a low likelihood of a physiologic role, as the Kd for binding is ~10,000 higher than the physiologic level of MG53 present in the serum of rodents and humans (~10 pM). Our findings question the notion proposed by Xiao and colleagues -whether targeting circulating MG53 opens a new therapeutic avenue for type 2 diabetes mellitus and its complications.
Keywords: Akt phosphorylation, C2C12 cells, type 2 diabetes mellitus, HepG2 cells, MG53/TRIM72, Mice, Myokines, Insulin receptor
Received: 29 Apr 2024; Accepted: 15 Aug 2024.
Copyright: © 2024 Lee, Nishi, Kim, Murayama, Dawson, Wang, Zhou, Tan, Cai, Takeshima and Park. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Kyung Eun Lee, University of Virginia, Charlottesville, United States
Miyuki Nishi, Kyoto University, Kyoto, 606-8501, Kyōto, Japan
Jongsoo Kim, University of Virginia, Charlottesville, United States
Xiaoliang Wang, University of Virginia, Charlottesville, United States
Hiroshi Takeshima, Kyoto University, Kyoto, 606-8501, Kyōto, Japan
Ki Ho Park, University of Virginia, Charlottesville, United States
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.