PT  - JOURNAL ARTICLE
AU  - Clothilde Philouze
AU  - Sophie Turban
AU  - Béatrice Cremers
AU  - Audrey Caliez
AU  - Gwladys Lamarche
AU  - Catherine Bernard
AU  - Nicolas Provost
AU  - Philippe Delerive
TI  - MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle
AID  - 10.1101/2020.12.24.424288
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.12.24.424288
4099  - http://biorxiv.org/content/early/2020/12/24/2020.12.24.424288.short
4100  - http://biorxiv.org/content/early/2020/12/24/2020.12.24.424288.full
AB  - In type 2 diabetes (T2D), both muscle and liver are severely resistant to insulin action. Muscle insulin resistance accounts for more than 80% of the impairment in total body glucose disposal in T2D patients and is often characterized by an impaired insulin signaling. Mitsugumin 53 (MG53), a muscle-specific TRIM family protein initially identified as a key regulator of cell membrane repair machinery has been suggested to be a critical regulator of muscle insulin signaling pathway by acting as ubiquitin E3 ligase targeting both the insulin receptor and insulin receptor substrate 1 (IRS1). Here, we show using in vitro and in vivo approaches that MG53 is not a critical regulator of insulin signaling and glucose homeostasis. First, MG53 expression is not consistently regulated in skeletal muscle from various preclinical models of insulin resistance. Second, MG53 gene knock-down in muscle cells does not lead to impaired insulin response as measured by Akt phosphorylation on Serine 473 and glucose uptake. Third, recombinant human MG53 does not alter insulin response in both differentiated C2C12 and human skeletal muscle cells. Fourth, ectopic expression of MG53 in HEK293 cells lacking endogenous MG53 expression fails to alter insulin response as measured by Akt phosphorylation. Finally, both male and female mg53 −/− mice were not resistant to high fat induced obesity and glucose intolerance compared to wild-type mice. Taken together, these results strongly suggest that MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle.