Changes in the Glutathione System in Response to Exercise Training are Sex‐Dependent in Humans

Background Glutathione is a ubiquitous tripeptide thiol that is vital to intra‐ and extra‐cellular maintenance of redox balance and signaling and the most common endogenous antioxidant found in every cell in the body. Glutamate Cysteine Ligase (GCL) is the rate limiting enzyme involved in the synthesis of glutathione and contributes heavily to the antioxidant defense system. The present RCT investigated age and sex differences in glutathione concentrations and GCL‐catalytic subunit (GCLC) protein abundance in response to an acute exercise trial before and after an 8‐week exercise intervention. Methods Older (≥60y, n=13) and younger (18–28y, n=13) men and women were randomized to an 8‐week exercise intervention (EX, n=16) or a non‐exercise control group (CON, n=10). Basal levels of reduced and oxidized glutathione (GSH:GSSG) were measured in erythrocyte lysate pre‐ and post‐intervention. GCLC protein abundance was measured in response to an acute exercise trial in peripheral blood mononuclear cells from blood samples collected at 7 time points (baseline, +10m, +30m, +1hr, +4hr, +8hr, and +24hr post‐exercise) before and after the intervention. Results Aerobic capacity improved in EX ( p =0.001), while CON did not change. These effects did not differ between sexes. Older individuals had significantly lower levels of GSH concentrations compared to young prior to the exercise intervention ( p = 0.05), but there were no differences between older and younger EX following the intervention. The exercise intervention elicited significant increases in GSH, while GSSG and GSH:GSSG did not change. When parsed by sex, the exercised‐induced increases in antioxidant content were only seen in women (p=0.045), and did not change in men. GCLC increased in response to the acute exercise trial in the whole cohort ( p =0.02), with no effects of age, sex, or intervention group. The exercise intervention elicited a trend for elevated GCLC protein content with no change in the controls. Interestingly, this exercise‐induced increase was mainly seen in men; older male exercisers showed increased GCLC protein content compared to inactive controls and younger male exercisers showed the same trend. However, women showed no increases in GCLC content compared to inactive controls and in fact had significantly lower GCLC following the exercise intervention ( p =0.039). Conclusion To our knowledge this is the first study to investigate the effect of an exercise intervention on glutathione and GCLC protein content. These preliminary data demonstrate that moderate exercise training increases GSH levels and GCLC in older adults, but in sex divergent manner. Support or Funding Information Funding: NIH R15AG055077Older and younger individuals were randomized to either 8‐weeks of exercise training or 8‐weeks as a control. Individuals were screened then performed a VO2 max test to determine fitness levels. Next the individuals performed an acute exercise trial where blood draws were taken prior to and time points following the acute exercise bout to measure GSH:GSSG and GCLC. Individuals were then randomized to the control or exercise group. Post testing was performed following the 8‐week intervention.GSH levels are significantly lower compared to younger individuals prior to an exercise intervention, following 8‐weeks of exercise GSH levels were restored to levels comparative to younger individuals.