The VAPB Point Mutation Associated With Amyotrophic Lateral Sclerosis Can Affect Myoblast Differentiation Through The IGF1-AKT Signaling Pathway

Skeletal muscle is an important component of human body and plays an important role in metabolic regulation.When muscle pathological changes,it will seriously affect people’s normal life.Amyotrophic lateral sclerosis(ALS)is a neurodegenerative muscle disease for which there is no particularly good treatment.VAPB is a kind of exist in the endoplasmic reticulum Ⅱ integrated membrane protein.It plays an irreplaceable role in lipid transfer and phospholipid metabolism,membrane transport,microtubule recombination,unfolded protein response,telomere silencing and other cellular functions.In recent years,several point mutants of VAPB have been identified in a number of patients with familial ALS,but the mechanism of these mutants in muscles has not been reported.Based on the previous study of VAPB in our laboratory,this paper conducted a preliminary study on the mechanism of these ALS-related VAPB point mutants in the differentiation of myoblasts.Rab5 is a small GTPase located in the early endosome,and the insulin receptor substrate protein IRS1 plays an important role in the IGF1-AKT signaling pathway.Preliminary studies in the laboratory have found that VAPB can interact with both Rab5 and IRS1.The combination of VAPB and Rab5 increases the stability of IRS1 and affects myoblast differentiation by affecting IGF1 signaling pathway.In this study,it was found that the VAPB point mutants associated with ALS accumulated in C2C12 myoblast cells,and the formation of such aggregation changed the normal structure of endoplasmic reticulum.These mutants could not interact with Rab5,and co-localization with IRS1 disappeared,which could not increase the stability of IRS1.Overexpression of wild-type VAPB in C2C12 cells can promote myoblast differentiation,while ALS-related VAPB point mutants cannot.This study was the first to integrate the currently reported VAPB point mutants associated with ALS and found that they were different from wild-type VAPB in promoting myoblast differentiation,which could help to better understand the pathogenesis of VAPB mutation in ALS.