Background: Sidt2 is an integral lysosomal membrane protein. Previously, we generated a Sidt2 global knockout mouse and found impaired insulin secretion, along with skeletal muscle pathology. Methods: A mouse model with a muscle-specific knockout of the Sidt2 gene (Sidt2(f/f)Cre) had been generated, to which extensive morphologic study as well as functional study was applied to investigate the direct role of Sidt2 on skeletal muscle tissue in vivo. Secondly, the autophagy-lysosomal pathway was examined by Western blot and immunostaining. Additionally, RNA expression changes in Sidt2(f/f)Cre mice were analyzed by genechip. Results: Sidt2 deficiency in skeletal muscle results in pathognomonic hallmarks of muscular dystrophy, including muscle mass decrease, muscle weakness, fibrosis, central nucleation, fiber regeneration, mildly elevated serum creatine kinase, and dramatically elevated sarcolipin mRNA. Along with accumulation of autophagolysomes, LC3-II, adaptor protein p62, ubiquitinated aggregates, and Lamp2-positive vacuoles were increased significantly in Sidt2(f/f)Cre skeletal muscle fibers. However, only lysosomal-related genes were upregulated, while the genes upstream of the autophagy pathway were unchanged. Simultaneously, the proteasome chymotryptic activity and the lysosomal soluble enzyme activity were unimpaired, which largely excluded the possibility of proteasome chymotryptic activity defect and the lysosomal soluble enzyme defect leading to ubiquitinated aggregates accumulation. Conclusion: We concluded that Sidt2 deficiency leads to muscular dystrophy-like phenotype in mice and Sidt2 plays a critical role in the late stage of autophagy. (C) 2018 Elsevier Inc. All rights reserved.
[1]Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Pediat Res, Pediat Endocrinol & Genet Metab,Xinhua Hosp, Kongjiang Rd 1665, Shanghai 200092, Peoples R China;
[2]Fudan Univ, Childrens Hosp, Dept Neurol, Shanghai, Peoples R China
(8.0+极速模式)