Chemerin-induced mitochondrial dysfunction in skeletal muscle

J Cell Mol Med. 2015 May;19(5):986-95. doi: 10.1111/jcmm.12487. Epub 2015 Mar 6.

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.

Keywords: autophagy; chemerin; mitochondrial dysfunction; skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Autophagy / genetics
  • Blotting, Western
  • Cell Line
  • Chemokines / genetics
  • Chemokines / metabolism*
  • Fluorescent Antibody Technique
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Insulin / pharmacology
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Membrane Potential, Mitochondrial / genetics
  • Mice, Inbred C57BL
  • Mitochondria, Muscle / genetics
  • Mitochondria, Muscle / metabolism*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Chemokines
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Reactive Oxygen Species
  • chemerin protein, mouse
  • Proto-Oncogene Proteins c-akt