Redox basis of exercise physiology

Abstract

Redox reactions control fundamental processes of human biology. Therefore, it is safe to assume that the responses and adaptations to exercise are, at least in part, mediated by redox reactions. In this review, we are trying to show that redox reactions are the basis of exercise physiology by outlining the redox signaling pathways that regulate four characteristic acute exercise-induced responses (muscle contractile function, glucose uptake, blood flow and bioenergetics) and four chronic exercise-induced adaptations (mitochondrial biogenesis, muscle hypertrophy, angiogenesis and redox homeostasis). Based on our analysis, we argue that redox regulation should be acknowledged as central to exercise physiology.

Keywords: Adaptations; Antioxidants; Exercise; Redox biology; Responses; Signaling.

Graphical abstract

Fig. 1

Proposed mechanisms on how RONS regulate muscle contractile function. Panel A based on [31,32]; Panel B based on [28,29,39] and [30]; Panel C based on [[42], [43], [44]]. GSH, reduced glutathione; H₂O₂, hydrogen peroxide; NO^•, nitric oxide; OH^•, hydroxyl radical; ONOO⁻, peroxynitrite; RYR, ryanodine receptors; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; SOD, superoxide dismutase; TnI, troponin I.

Fig. 2

Proposed mechanisms on how RONS regulate tissue glucose uptake. Panel A based on [98,101,108]; Panel B based on [[69], [77], [410]]. CaMK, Ca²⁺/calmodulin-dependent protein kinase; MAPK, mitogen-activated protein kinase; RONS, reactive oxygen and nitrogen species.

Fig. 3

Proposed mechanisms on how RONS regulate blood flow. Based on [[117], [138], [412]] and [111]. cGMP, cyclic guanosine monophosphate; H₂O₂, hydrogen peroxide; MAPK, mitogen-activated protein kinase; NO^•, nitric oxide; O^•-, superoxide radical.

Fig. 4

A representative example of the interplay between cellular energy metabolism and redox homeostasis. At rest, glucose is directed mainly towards glycolysis, whereas under increased oxidative stress conditions, ROS inactivate GAPDH, as a first-line metabolic response, and carbohydrate flux is dynamically rerouted to the pentose phosphate pathway to produce NADPH (the major reductant of key antioxidant enzymes). Based on [[177], [178], [179]]. G6PD, glucose-6-phosphate dehydrogenase; GAPDH, reduced glyceraldehyde 3-phosphate dehydrogenase; NADPH, reduced nicotinamide adenine dinucleotide phosphate; PPP, pentose phosphate pathway; RONS, reactive oxygen and nitrogen species.

Fig. 5

Proposed mechanisms on how RONS regulate mitochondrial biogenesis. Panel A based on [188,[238], [239], [240]]; Panel B based on [[241], [242], [243]]; Panel C based on [245,247]. AMPK, 5′ AMP-activated protein kinase; cGMP, cyclic guanosine monophosphate; H₂O₂, hydrogen peroxide; LKB1, liver kinase B1; NO^•, nitric oxide; Nrf2, nuclear factor erythroid 2-related factor 2; ONOO⁻, peroxynitrite; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; RONS, reactive oxygen and nitrogen species.

Fig. 6

Proposed mechanisms on how RONS regulate muscle hypertrophy. Based on [258,263,267] and [259]. Akt, protein kinase B; ERK, extracellular signal-regulated kinase; H₂O₂, hydrogen peroxide; IGF-I, insulin-like growth factor 1; mTOR, mammalian target of rapamycin; NO^•, nitric oxide; O^•-, superoxide radical; ONOO⁻, peroxynitrite; p70^S6K, ribosomal protein S6 kinase beta-1; SOD, superoxide dismutase; Trpv1, transient receptor potential cation channel subfamily V member 1.

Fig. 7

Proposed mechanisms on how RONS regulate angiogenesis. Based on [280,282,296,315,317] and [287]. c-Src, proto-oncogene tyrosine-protein kinase; ERK, extracellular signal-regulated kinase; HIF-1α, hypoxia-inducible factor 1-alpha; JNK, c-Jun N-terminal kinases; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells; Rac1, Ras-related C3 botulinum toxin substrate 1; RONS, reactive oxygen and nitrogen species; VEGF, vascular endothelial growth factor.

Fig. 8

Proposed mechanisms on how RONS regulate redox homeostasis. Panel A based on [9,318]; Panel B based on [344,372]; Panel C based on [255,370]. ARE, antioxidant response element; DNA, deoxyribonucleic acid; IKK, IκB kinase; Keap1, Kelch-like ECH-associated protein 1; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid 2-related factor 2; OGG1, 8-oxoguanine glycosylase; ROS, reactive oxygen species.

Fig. 9

A summary figure illustrating the central RONS, types of redox modifications and molecules involved in the 4 acute exercise-induced responses (muscle contractile function, glucose uptake, blood flow and cell bioenergetics) and the 4 training-induced adaptations described in the present review. AMPK, 5′ AMP-activated protein kinase; c-Src, proto-oncogene tyrosine-protein kinase; cGMP, cyclic guanosine monophosphate; G6PD, glucose-6-phosphate dehydrogenase; GAPDH, reduced glyceraldehyde 3-phosphate dehydrogenase; H₂O₂, hydrogen peroxide; HIF-1α, hypoxia-inducible factor 1-alpha; IGF-I, insulin-like growth factor 1; IKK, IκB kinase; Keap1, Kelch-like ECH-associated protein 1; LKB1, liver kinase B1; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO^•, nitric oxide; Nrf2, nuclear factor erythroid 2-related factor 2; O^•-, superoxide radical; OGG1, 8-oxoguanine glycosylase; ONOO⁻, peroxynitrite; p70^S6K, ribosomal protein S6 kinase beta-1; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PTM, post-translational modifications; RYR, ryanodine receptors; Trpv1, transient receptor potential cation channel subfamily V member 1; VEGF, vascular endothelial growth factor.