Genetic ablation of 12/15-lipoxygenase but not 5-lipoxygenase protects against denervation-induced muscle atrophy

Arunabh Bhattacharya, Ryan Hamilton, Amanda Jernigan, Yiqiang Zhang, Marian Sabia, Md M. Rahman, Yan Li, Rochelle Wei, Asish Chaudhuri, Holly Van Remmen

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Skeletal muscle atrophy is a debilitating outcome of a number of chronic diseases and conditions associated with loss of muscle innervation by motor neurons, such as aging and neurodegenerative diseases. We previously reported that denervation-induced loss of muscle mass is associated with activation of cytosolic phospholipase A2 (cPLA2), the rate-limiting step for the release of arachidonic acid from membrane phospholipids, which then acts as a substrate for metabolic pathways that generate bioactive lipid mediators. In this study, we asked whether 5- and 12/15-lipoxygenase (LO) lipid metabolic pathways downstream of cPLA2 mediate denervation-induced muscle atrophy in mice. Both 5- and 12/15-LO were activated in response to surgical denervation; however, 12/15-LO activity was increased ~2.5-fold versus an ~1.5-fold increase in activity of 5-LO. Genetic and pharmacological inhibition of 12/15-LO (but not 5-LO) significantly protected against denervation-induced muscle atrophy, suggesting a selective role for the 12/15-LO pathway in neurogenic muscle atrophy. The activation of the 12/15-LO pathway (but not 5-LO) during muscle atrophy increased NADPH oxidase activity, protein ubiquitination, and ubiquitin-proteasome-mediated proteolytic degradation. In conclusion, this study reveals a novel pathway for neurogenic muscle atrophy and suggests that 12/15-LO may be a potential therapeutic target in diseases associated with loss of innervation and muscle atrophy.

Original languageEnglish (US)
Pages (from-to)30-40
Number of pages11
JournalFree Radical Biology and Medicine
Volume67
DOIs
StatePublished - Jan 1 2014

Keywords

  • 12/15-Lipoxygenase
  • 5-Lipoxygenase
  • Denervation
  • Free radicals
  • Muscle atrophy
  • NADPH oxidase

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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