Hedges 2020 Biosci Rep

Hedges CP, Pham T, Shetty B, Masson SWC, Hickey AJR, Shepherd PR, Merry TL (2020) Prolonged treatment with a PI3K p110α inhibitor causes sex- and tissue-dependent changes in antioxidant content, but does not affect mitochondrial function. https://doi.org/10.1042/bsr20201128

» Biosci Rep 40:BSR20201128. PMID: 33006363 Open Access

Hedges CP, Pham T, Shetty B, Masson SWC, Hickey AJR, Shepherd PR, Merry TL (2020) Biosci Rep

Abstract: Genetic inhibition of the p110α isoform of phosphatidylinositol-3-kinase (PI3K) can increase murine lifespan, enhance mitochondrial function and alter tissue-specific oxidative balance. Here, we investigated whether pharmacological inhibition of the p110α isoform of PI3K induces similar enhancement of mitochondrial function in middle-aged mice. Eight-month-old male and female mice were fed a diet containing 0.3 g/kg of the p110α-selective inhibitor BYL-719 (BYL) or a vehicle diet (VEH) for 6 weeks. Mice consuming BYL-719 had higher blood glucose and insulin, and tended towards decreased body weight. After 72 h, gene expression of the mitochondrial biogenesis mediators Pgc1α, Tfam and Nrf1 was greater in liver of BYL-719 males only, but unchanged in skeletal muscle of either sex. Six weeks of BYL-719 treatment did not affect mitochondrial content or function in the liver or skeletal muscle of either sex. In livers of males only, the expression of the antioxidant genes Nfe2l2, Cat, Sod1 and Sod2 increased within 72 h of BYL-719 treatment, and remained higher after 6 weeks. This was associated with an increase in hepatic GSH content and catalase protein expression, and lower H₂O₂ levels. Our results suggest that pharmacological inhibition of p110α in adult mice does not affect liver or skeletal muscle mitochondrial function, but does show sex- and tissue-specific effects on up-regulation of antioxidant response. • Keywords: BYL-719, Free radicals, Mitochondrial respiration, Oxidative stress, Phosphoinositide 3-kinase • Bioblast editor: Plangger M

Labels: MiParea: Respiration, Pharmacology;toxicology 

Organism: Mouse  Tissue;cell: Skeletal muscle, Liver  Preparation: Permeabilized tissue 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, CIV, NS, ROX  HRR: Oxygraph-2k, O2k-Fluorometer 

2023-01, AmR