title: Chemerin-induced mitochondrial dysfunction in skeletal muscle.
abstract: Chemerin is a novel adipocyte-derived factor that induces insulin resistance in skeletal muscle. However, the effect of chemerin on skeletal muscle mitochondrial function has received little attention. In the present study, we investigated whether mitochondrial dysfunction is involved in the pathogenesis of chemerin-mediated insulin resistance. In this study, we used recombinant adenovirus to express murine chemerin in C57BL/6 mice. The mitochondrial function and structure were evaluated in isolated soleus muscles from mice. The oxidative mechanism of mitochondrial dysfunction in cultured C2C12 myotubes exposed to recombinant chemerin was analysed by western blotting, immunofluorescence and quantitative real-time polymerase chain reaction. The overexpression of chemerin in mice reduced the muscle mitochondrial content and increased mitochondrial autophagy, as determined by the increased conversion of LC3-I to LC3-II and higher expression levels of Beclin1 and autophagy-related protein-5 and 7. The chemerin treatment of C2C12 myotubes increased the generation of mitochondrial reactive oxygen species, concomitant with a reduced mitochondrial membrane potential and increased the occurrence of mitochondrial protein carbonyls and mitochondrial DNA deletions. Knockdown of the expression of chemokine-like receptor 1 or the use of mitochondria-targeting antioxidant Mito-TEMPO restored the mitochondrial dysfunction induced by chemerin. Furthermore, chemerin exposure in C2C12 myotubes not only reduced the insulin-stimulated phosphorylation of protein kinase B (AKT) but also dephosphorylated forkhead box O3α (FoxO3α). Chemerin-induced mitochondrial autophagy likely through an AKT-FoxO3α-dependent signalling pathway. These findings provide direct evidence that chemerin may play an important role in regulating mitochondrial remodelling and function in skeletal muscle.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Qihai
authors.initials: Q
authors.lastname: Xie
authors.forename: Yujie
authors.initials: Y
authors.lastname: Deng
authors.forename: Chenglin
authors.initials: C
authors.lastname: Huang
authors.forename: Penghao
authors.initials: P
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Weili
authors.initials: W
authors.lastname: Shen
authors.forename: Pingjin
authors.initials: P
authors.lastname: Gao
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001343:Autophagy / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007328:Insulin / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018925:Chemokines; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; C523686:chemerin protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: autophagy; chemerin; mitochondrial dysfunction; skeletal muscle