Journal Article

Rab5a activates IRS1 to coordinate IGF-AKT-mTOR signaling and myoblast differentiation during muscle regeneration

Cong, Xiao Xia, Gao, Xiu Kui, Shen, Wei Liang, Zheng, Li Ling, Shen, Yue, Meng, Zhuo Xian, Shi, Yin Pu, He, Min Yi, Low, Boon Chuan, Liang, Yong Heng, Zheng, Ming Zhu, Ouyang, Hongwei, Lu, Lin Rong, Zhou, Yi Ting, Hu, Ping, Ke, Yue Hai, Liu, Xiao Ceng, Wen, Jie, Rao, Xi Sheng

2020

Overview

Rab5 is a master regulator for endosome biogenesis and transport while its in vivo physiological function remains elusive. Here, we find that Rab5a is upregulated in several in vivo and in vitro myogenesis models. By generating myogenic Rab5a-deficient mice, we uncover the essential roles of Rab5a in regulating skeletal muscle regeneration. We further reveal that Rab5a promotes myoblast differentiation and directly interacts with insulin receptor substrate 1 (IRS1), an essential scaffold protein for propagating IGF signaling. Rab5a interacts with IRS1 in a GTP-dependent manner and this interaction is enhanced upon IGF-1 activation and myogenic differentiation. We subsequently identify that the arginine 207 and 222 of IRS1 and tyrosine 82, 89, and 90 of Rab5a are the critical amino acid residues for mediating the association. Mechanistically, Rab5a modulates IRS1 activation by coordinating the association between IRS1 and the IGF receptor (IGFR) and regulating the intracellular membrane targeting of IRS1. Both myogenesis-induced and IGF-evoked AKT-mTOR signaling are dependent on Rab5a. Myogenic deletion of Rab5a also reduces the activation of AKT-mTOR signaling during skeletal muscle regeneration. Taken together, our study uncovers the physiological function of Rab5a in regulating muscle regeneration and delineates the novel role of Rab5a as a critical switch controlling AKT-mTOR signaling by activating IRS1.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/109 / 13/95 / 14/19 / 42/89 / 631/208/135 / 631/80 / 64/60 / AKT protein / Amino acids / Apoptosis / Arginine / Biochemistry / Biomedical and Life Sciences / Cell Biology / Cell Cycle Analysis / Endosomes / Guanosine triphosphate / Insulin / Insulin receptor substrate 1 / Insulin-like growth factor I / Intracellular signalling / Life Sciences / Musculoskeletal system / Myoblasts / Myogenesis / Physiology / Skeletal muscle / Stem Cells / TOR protein / Tyrosine