Metabolomic and flux-balance analysis of age-related decline of hypoxia tolerance in Drosophila muscle tissue

TL;DR

This study combines metabolomics and flux-balance modeling to investigate how aging impairs hypoxia tolerance in Drosophila muscle, revealing age-related declines in mitochondrial recovery and shifts in energy metabolism.

Contribution

It expands existing metabolic models with age-specific data and demonstrates how aging affects hypoxia recovery mechanisms in fruit flies.

Findings

Aging reduces hypoxia tolerance in Drosophila.

Decreased ATP recovery linked to impaired mitochondrial respiration.

Older flies rely more on acetate production during reoxygenation.

Abstract

The fruit fly D. melanogaster is increasingly used as a model organism for studying acute hypoxia tolerance and for studying aging, but the interactions between these two factors are not well known. Here we show that hypoxia tolerance degrades with age in post-hypoxic recovery of whole-body movement, heart rate and ATP content. We previously used 1H NMR metabolomics and a constraint-based model of ATP-generating metabolism to discover the end products of hypoxic metabolism in flies and generate hypotheses for the biological mechanisms. We expand the reactions in the model using tissue- and age-specific microarray data from the literature, and then examine metabolomic profiles of thoraxes after 4 hours at 0.5% O2 and after 5 minutes of recovery in 40- versus 3-day-old flies. Model simulations were constrained to fluxes calculated from these data. Simulations suggest that the decreased ATP production during reoxygenation seen in aging flies can be attributed to reduced recovery of mitochondrial respiration pathways and concomitant over-dependence on the acetate production pathway as an energy source.