Angiotensin-II-induced Muscle Wasting is Mediated by 25-Hydroxycholesterol via GSK3β Signaling Pathway

EBioMedicine. 2017 Feb:16:238-250. doi: 10.1016/j.ebiom.2017.01.040. Epub 2017 Jan 30.

Abstract

While angiotensin II (ang II) has been implicated in the pathogenesis of cardiac cachexia (CC), the molecules that mediate ang II's wasting effect have not been identified. It is known TNF-α level is increased in patients with CC, and TNF-α release is triggered by ang II. We therefore hypothesized that ang II induced muscle wasting is mediated by TNF-α. Ang II infusion led to skeletal muscle wasting in wild type (WT) but not in TNF alpha type 1 receptor knockout (TNFR1KO) mice, suggesting that ang II induced muscle loss is mediated by TNF-α through its type 1 receptor. Microarray analysis identified cholesterol 25-hydroxylase (Ch25h) as the down stream target of TNF-α. Intraperitoneal injection of 25-hydroxycholesterol (25-OHC), the product of Ch25h, resulted in muscle loss in C57BL/6 mice, accompanied by increased expression of atrogin-1, MuRF1 and suppression of IGF-1/Akt signaling pathway. The identification of 25-OHC as an inducer of muscle wasting has implications for the development of specific treatment strategies in preventing muscle loss.

Keywords: Angiotensin II; Cardiac cachexia; Ch25h; Heart failure; TNF-α.

MeSH terms

  • Angiotensin II
  • Animals
  • Blotting, Western
  • Cell Line
  • Cells, Cultured
  • Gene Expression Profiling / methods
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Hydroxycholesterols
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscular Atrophy / chemically induced
  • Muscular Atrophy / metabolism*
  • Muscular Atrophy / prevention & control
  • Myoblasts / cytology
  • Myoblasts / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Signal Transduction*
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism
  • Thiadiazoles / pharmacology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
  • Hydroxycholesterols
  • Muscle Proteins
  • Receptors, Tumor Necrosis Factor, Type I
  • Thiadiazoles
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Angiotensin II
  • Insulin-Like Growth Factor I
  • 25-hydroxycholesterol
  • Steroid Hydroxylases
  • cholesterol 25-hydroxylase
  • Fbxo32 protein, mouse
  • SKP Cullin F-Box Protein Ligases
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt