Increased fatty acid metabolism and decreased glycolysis are hallmarks of metabolic reprogramming within microglia in degenerating white matter during recovery from experimental stroke

Sanna H. Loppi, Marco A. Tavera-Garcia, Danielle A. Becktel, Boaz K. Maiyo, Kristos E. Johnson, Thuy Vi V. Nguyen, Rick G. Schnellmann, Kristian P. Doyle

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

The goal of this study was to evaluate changes in metabolic homeostasis during the first 12 weeks of recovery in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we compared the brain metabolomes of ipsilateral and contralateral hemispheres from aged male mice up to 12 weeks after stroke to that of age-matched naïve and sham mice. There were 707 biochemicals detected in each sample by liquid chromatography-mass spectroscopy (LC-MS). Mitochondrial fatty acid β-oxidation, indicated by acyl carnitine levels, was increased in stroked tissue at 1 day and 4 weeks following stroke. Glucose and several glycolytic intermediates were elevated in the ipsilateral hemisphere for 12 weeks compared to the aged naïve controls, but pyruvate was decreased. Additionally, itaconate, a glycolysis inhibitor associated with activation of anti-inflammatory mechanisms in myeloid cells, was higher in the same comparisons. Spatial transcriptomics and RNA in situ hybridization localized these alterations to microglia within the area of axonal degeneration. These results indicate that chronic metabolic differences exist between stroked and control brains, including alterations in fatty acid metabolism and glycolysis within microglia in areas of degenerating white matter for at least 12 weeks after stroke.

Original languageEnglish (US)
Pages (from-to)1099-1114
Number of pages16
JournalJournal of Cerebral Blood Flow and Metabolism
Volume43
Issue number7
DOIs
StatePublished - Jul 2023

Keywords

  • glycolysis
  • itaconate
  • metabolism
  • stroke
  • β-Oxidation

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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