Noninsulin-dependent diabetes mellitus (type 2 diabetes) is becoming an epidemic disease due to the increased incidence of obesity. Mitsugumin 53 (MG53), tripartite motif-containing protein 72 (TRIM72), larges exist in skeletal muscle. MG53 contains a tripartite domain (an E3 ligase RING domain, a B-box, and two coiled-coil domains) and a SPRY domain. IGF-1 initiates MyoD activation via an IGFR-PI3K-Akt pathway during skeletal myogenesis.

Small molecule MG53 inhibitor development takes the two sides: an E3 ligase for IRS-1 ubiquitination and membrane repair into consideration. However, simple MG53 inhibition may lead to impaired-membrane repair in cardiac and skeletal muscle cells after acute injury. 

In this article, we will introduce an MG53-IRS-1 interaction disruptor (MID), MID-1.

MID-1 is a disruptor of MG53-IRS-1 (Mitsugumin 53-insulin receptor substrate-1) interaction. MID-1 disrupts the molecular association of MG53 with IRS-1 and abolishes MG53-induced IRS-1 ubiquitination and degradation in skeletal muscle, leading to elevated IRS-1 expression level and increased insulin signaling and glucose uptake. 

In C2C12 myotubes, MID-1increases the IRS-1 expression level in skeletal muscle by disrupting the MG53-IRS-1 interaction. At the same time, this compound also decreases IRS-1 and MG53 protein levels significantly. 

MID-1 reduces the luciferase activity in HEK 293 cell lines expressing NLUC-IRS-1 and CLUC-C14A.

Furthermore, the MG132-induced MG53-IRS-1 interaction signal disappears with the inclusion of MID-1. But the MG132-induced MG53-FAK interaction signal does not appears. This result shows that MID-1 disrupts the MG53-IRS-1 interaction but not MG53-FAK interaction. Besides, in HEK 293 cells, MG53 oligomer formation by reciprocal co-immunoprecipitation after HA-MG53 and Myc-MG53 co-expression. MID-1 does not affect MG53 oligomerization in vitro. 

In HEK 293 cells, MID-1 abolishes MG53-induced IRS-1 ubiquitination and degradation. Additionally, in C2C12 myotubes, MID-1 increases insulin signaling and insulin-elicited glucose uptake, as well as skeletal myogenesis. 

 Although MID-1 exhibits good activity in vitro. But it does not have good pharmacokinetics. MID-1 fails to ameliorate insulin resistance in vivo. 

In conclusion, MID-1 is a potent MG53-IRS-1 interaction inhibitor. And there needs to prepare various MID-1 derivatives which could ameliorate insulin resistance in obesity and diabetes animal models.

Reference:

[1]  Lee H, et, al. J Biol Chem. 2016 Dec 23;291(52):26627-26635.