An unexplored role for Peroxiredoxin in exercise-induced redox signalling?

Abstract

Peroxiredoxin (PRDX) is a ubiquitous oxidoreductase protein with a conserved ionised thiol that permits catalysis of hydrogen peroxide (H2O2) up to a million times faster than any thiol-containing signalling protein. The increased production of H2O2 within active tissues during exercise is thought to oxidise conserved cysteine thiols, which may in turn facilitate a wide variety of physiological adaptations. The precise mechanisms linking H2O2 with the oxidation of signalling thiol proteins (phosphates, kinases and transcription factors) are unclear due to these proteins' low reactivity with H2O2 relative to abundant thiol peroxidases such as PRDX. Recent work has shown that following exposure to H2O2 in vitro, the sulfenic acid of the PRDX cysteine can form mixed disulphides with transcription factors associated with cell survival. This implicates PRDX as an ‘active’ redox relay in transmitting the oxidising equivalent of H2O2 to downstream proteins. Furthermore, under oxidative stress, PRDX can form stable oxidised dimers that can be secreted into the extracellular space, potentially acting as an extracellular ‘stress’ signal. There is extensive literature assessing non-specific markers of oxidative stress in response to exercise, however the PRDX catalytic cycle may offer a more robust approach for measuring changes in redox balance following exercise. This review discusses studies assessing PRDX-mediated cellular signalling and integrates the recent advances in redox biology with investigations that have examined the role of PRDX during exercise in humans and animals. Future studies should explore the role of PRDX as a key regulator of peroxide mediated-signal transduction during exercise in humans.

Redox Mechanism of Reactive Oxygen Species in Exercise

“…Exercise-induced ROS also plays a role in adaptation through the oxidation of cysteine residue in various proteins. For example, cysteine-rich peroxiredoxin, an antioxidant responsible for H 2 O 2 catalysis, is oxidized and formed stable dimers in response to elevated H 2 O 2 levels during exercise, managing H 2 O 2 gradients and regulating extracellular redox-signaling (Wadley et al, 2016). Moreover, the disulfide bonds formed by oxidized cysteine residues likely enhance protein synthesis in active individuals (Buresh and Berg, 2015).…”

Exercise redox biochemistry: Conceptual, methodological and technical recommendations

“…Redox signalling regulates essential cellular processes from apoptosis to metabolism [58]. Whilst redox signalling may regulate exercise responses and adaptations (reviewed in [59], [60], [61], [62], [63], [64]), the underpinning chemistry is ill-defined [59]. For example, whether O 2 .− mediated thiol oxidation contributes is unclear [65].…”

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

“…It is important to recognize that the rate constants within these protein families and isoforms can vary by up to 10 6  M −1  s −1 ,149 suggesting that the concentration of H 2 O 2 and the enzymes that regulate it play a significant role in redox signalling. PRX proteins have been shown to play a role in transmitting redox signals into a dynamic biological response and to have subtle changes in both abundance and oxidative state with age 52, 150, 151. PRXII has recently been found to form an interdisulfide with STAT3 in response to cytokines, suggesting that it plays an important regulatory role 152…”

“…PRX proteins have been shown to play a role in transmitting redox signals into a dynamic biological response and to have subtle changes in both abundance and oxidative state with age. 52,150,151 PRXII has recently been found to form an interdisulfide with STAT3 in response to cytokines, suggesting that it plays an important regulatory role. 152…”