title: Palmitate increases musclin gene expression through activation of PERK signaling pathway in C2C12 myotubes.
abstract: Musclin is a type of muscle-secreted cytokine and its increased gene expression induces insulin resistance in type 2 diabetes. However, the mechanism underlying increased musclin gene expression is currently unclear. Excessive saturated fatty acids (SFA) can activate the secretion of several muscle-secreted cytokines as well as endoplasmic reticulum (ER) stress pathway, thereby contributing to the development of type 2 diabetes. The purpose of this study was to investigate the mechanisms responsible for the effect of palmitate, the most abundant SFA in the plasma, on the gene expression of musclin in C2C12 myotubes. Treatment of C2C12 myotubes with palmitate or tunicamycin significantly increased the expression of musclin as well as ER stress-related genes, but treatment with oleate did not. Pre-treatment of C2C12 myotubes with 4-phenyl butyrate suppressed the expression of ER stress-related genes, simultaneously, resulting in decreased expression of the musclin gene induced by palmitate or tunicamycin. These results indicate that ER stress is related to palmitate-induced musclin gene expression. Moreover, palmitate-induced musclin gene expression was significantly inhibited in C2C12 myotubes when PERK pathway signaling was suppressed by knockdown of the PERK gene or treatment with GSK2656157, a PERK autophosphorylation inhibitor. However, there was no difference in the palmitate-induced musclin gene expression when IRE1 and ATF6 signaling pathways were suppressed by knockdown of the IRE1 and ATF6 genes. These findings suggest that palmitate increases musclin gene expression via the activation of the PERK signaling pathway in C2C12 myotubes.
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. Electronic address: guning@hit.edu.cn.
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Guo
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Mao
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Hu
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Sanli
authors.initials: S
authors.lastname: Jin
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: He
authors.affiliation: Faculty of Education, Wakayama University, Wakayama, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Oh
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Chuanpeng
authors.initials: C
authors.lastname: Liu
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000818:Animals; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics*; D019308:Palmitic Acid / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D019308:Palmitic Acid; D014157:Transcription Factors; D019892:eIF-2 Kinase; C498449:Ostn protein, mouse
keywords: ER stress; Musclin; PERK; Palmitate; Unfolded protein response (UPR)