Prolonged treatment with a PI3K p110α inhibitor causes sex- and tissue-dependent changes in antioxidant content, but does not affect mitochondrial function.

Christopher P Hedges,Troy L Merry,Toan Pham,Anthony J.R Hickey,Peter R Shepherd,Bhoopika Shetty,Stewart W.C Masson

doi:10.1042/bsr20201128

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.

Highlights

Mitochondria play a central role in coordinating cellular homoeostasis [1], and are putative mediators of health and disease, with mitochondrial dysfunction associated with the ageing process [2,3], and the development of many disease states [4,5,6,7,8]
Oncogenic mutations in PI3K has led to the development of isoform-specific pharmacological inhibitors of PI3K that are currently approved for clinical trials, and we have previously shown that daily i.p. administration of the PI3K p110α isoform inhibitor A66 is tolerated by young (4–5 weeks old) mice, but may lead to developmental defects in bone strength, and reduce fat and body mass gain, without altering insulin sensitivity [23]
To determine the effectiveness of BYL-719 consumed in diet to acutely impair glucose homoeostasis, a marker of PI3K inhibition in this context, blood glucose (Figure 1A) and plasma insulin (Figure 1B) were measured in a fed state 7 days after consuming BYL-719 in the diet

Summary

Introduction

Mitochondria play a central role in coordinating cellular homoeostasis [1], and are putative mediators of health and disease, with mitochondrial dysfunction associated with the ageing process [2,3], and the development of many disease states [4,5,6,7,8]. Mice which lack the insulin receptor in adipose tissue showed increased lifespan [9], and this is associated with increased mitochondrial gene expression and oxidative metabolism [10]. Heterozygous mutation of phosphatidylinositol-3-kinase (PI3K), which renders the p110α isoform catalytically inactive, results in mice that display normal glucose homoeostasis and insulin sensitivity with age, and increased lifespan [11]. Mice homozygous for this mutation are non-viable [12], providing evidence that while suppressing p110α activity does not result in an overt diabetic phenotype, some residual activity is required to maintain cellular homoeostasis.

Methods

Results

Conclusion