GSE131955
Nogo maintains muscle integrity and regulates muscle regeneration via modulating Nogo-A expression
Nogo, also called RTN4, functions through three isoforms including Nogo-A, -B, and -C. Although Nogo-A is a well-known CNS inhibitor and the level of Nogo-A is increased in muscles of ALS patients, its role in the regulation of skeletal muscle homeostasis and regeneration is still vague. In this study, we analyzed various pathological muscle condition of human and mouse model, and discovered significant increase of Nogo-A and myogenic factors. To understand the role of Nogo in skeletal muscle, muscle transcripts from Nogo+/+ and Nogo-/- mouse were analyzed and observed intensified gene expression involved in adipocyte differentiation and lipid metabolism, and reduced gene expression related to muscle differentiation and structure organization suggesting muscle disorder from muscle replacement with fat deposition. Skeletal muscle structure from Nogo null mice displayed dystrophic phenotypes including impaired myofiber structure and immune cell infiltrations, and dysregulated homeostatic features such as higher level of MyoD, procaspase 3, CHOP, and AKT compared to wild-type muscle. Notexin-injured Nogo deficient muscle resulted higher level of immune cell infiltration but defective in IL-6 production, a well-known myokine from immune cells, and abnormally upregulated regenerative muscle fibers than normal muscle. Therefore we hypothesized that increased Nogo-A in pathological conditions may regulate muscle regeneration. Then differentiating C2C12 cells and induced myogenic stem cells(iMSC) showed upregulated Nogo-A and Myogenin, and Nogo-A silencing in C2C12 cells abrogated the capability to differentiate into myotubes. In conclusion, Nogo functions to maintain muscle homeostasis and integrity, and altered Nogo-A expression in pathological muscle condition mediates muscle regeneration. These understanding suggests Nogo-A as a novel differentiation target for the treatment of myopathies at clinical set. Overall design: mRNA expression profiles of gastrocnemius muscle tissues of WT and Nogo KO mice were examined by Illumina Hi-seq 2500