Oxygen consumption and usage during physical exercise: the balance between oxidative stress and ROS-dependent adaptive signaling

Abstract

The complexity of human DNA has been affected by aerobic metabolism, including endurance exercise and oxygen toxicity. Aerobic endurance exercise could play an important role in the evolution of Homo sapiens, and oxygen was not important just for survival, but it was crucial to redox-mediated adaptation. The metabolic challenge during physical exercise results in an elevated generation of reactive oxygen species (ROS) that are important modulators of muscle contraction, antioxidant protection, and oxidative damage repair, which at moderate levels generate physiological responses. Several factors of mitochondrial biogenesis, such as peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), mitogen-activated protein kinase, and SIRT1, are modulated by exercise-associated changes in the redox milieu. PGC-1α activation could result in decreased oxidative challenge, either by upregulation of antioxidant enzymes and/or by an increased number of mitochondria that allows lower levels of respiratory activity for the same degree of ATP generation. Endogenous thiol antioxidants glutathione and thioredoxin are modulated with high oxygen consumption and ROS generation during physical exercise, controlling cellular function through redox-sensitive signaling and protein-protein interactions. Endurance exercise-related angiogenesis, up to a significant degree, is regulated by ROS-mediated activation of hypoxia-inducible factor 1α. Moreover, the exercise-associated ROS production could be important to DNA methylation and post-translation modifications of histone residues, which create heritable adaptive conditions based on epigenetic features of chromosomes. Accumulating data indicate that exercise with moderate intensity has systemic and complex health-promoting effects, which undoubtedly involve regulation of redox homeostasis and signaling.

FIG. 1.

The suggested effects of endurance capacity-mediated evolution on the human body. Early human endurance running was important for successful hunting, and high endurance capacity affected metabolism and redox adaptation. On the other hand, modern lifestyle physical inactivity acts against the build-up of endurance capacity. A low level of maximal oxygen uptake is a risk factor for a number of diseases and increases the rate of mortality. VO2max., maximal oxygen uptake.

FIG. 2.

There is a strong relationship between the rate of metabolism, ROS formation, and redox homeostasis. In the present review, we are focusing on those regulatory systems that are influenced by both metabolism and exercise. Exercise results in a significant increase in the metabolism of skeletal muscle, and moderate elevation in cerebral metabolism. On the other hand, blood flow and metabolism are significantly decreased in the liver and kidney during exercise. The antioxidant capacity and the resistance against oxidative stress increase in all of these organs. ROS, reactive oxygen species. (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)

FIG. 3.

This figure shows the hypothetical adaptive range. The middle of the graph represents the optimal zone of the dynamic homeostasis, while the outer line indicates the biological limitations, which cannot be reached without extreme risk of death. The line, called functional limitation, shows the capacity of each individual, and it is a mobile value. The functional/actual limit can be readily altered by exercise training. Aging decreases the rate of adaptive response, and the capacity to maintain homeostasis is decreasing, as demonstrated by the white arrows. Dotted arrows indicate the flexibility of functional limitation. (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)

FIG. 4.

The adaptive response to a single bout of exercise is limited, and oxidative damage often occurs. Moderate levels of oxidative damage could be important to the induction of the oxidative damage repair system. The regular exercise induced adaptation, due to the intermittent feature of exercise and rest periods, allows induction of the antioxidant and damage repair systems, which results in enhanced protection against oxidative stress, attenuates the aging process, and promotes health with increased functional capacities. MDA, malondialdehyde; RCD, reactive carbonyl derivatives; 8-OHdG, 8-hydroxy-2′-deoxyguanosine. (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)

FIG. 5.

Thiols are important antioxidants, and the GSH/GSSG ratio modulates vital cellular processes, including antioxidant systems, apoptosis, cellular growth, and signal transduction among others. Thiols are involved in the extracellular and intracellular oxidative defense, including the mitochondrial and nuclear compartments (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.) GSH, glutathione; GSSG, disulfide glutathione; TRX, thioredoxin.

FIG. 6.

The free radical-dependent aging theory is well accepted, and it is clearly demonstrated that the extent of oxidative damage increases in the last quarter of the life span. However, it is also clear that the oxidative modification of lipids, proteins, and DNA is well detectable even at a young age, and this could indicate that a moderate level of oxidative damage is not dangerous to cells; moreover, it even can be necessary. On the other hand, significant elevation of oxidative damage at an advanced age is associated with increased incidence of a wide range of diseases and impaired physiological function. Regular exercise has been shown to attenuate the age-associated increase in oxidative damage, and it also attenuates the deleterious effects of aging on organ function (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)

FIG. 7.

Lipid peroxidation byproducts, carbonyl groups, and the 8-oxoG levels are easily detectable, suggesting that these ROS-induced modifications could be necessary for cells. Lipid peroxidation can be induced by enzymatic processes and could be important to membrane remodeling. Carbonylation of amino acid residues could be an important mediator of protein turnover, since carbonylation can serve as a tag for proteolytic degradation. 8-oxoG is necessary for transcription of specific genes and for the opening of chromatin (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.) 8-oxoG, 8-Oxo-7,8 dihydroguanine; OGG1, 8-oxoguanine-DNA glycosylase.

FIG. 8.

Sirtuins are NAD⁺-dependent histone deacetylases and sensitive markers of metabolic and redox processes. SIRT-mediated deacetylation of target proteins is involved in metabolic processes, biogenesis of mitochondria, oxygen sensing, inflammation, apoptosis, and epigenetics, among others. Factors that are modifying redox balance, such as aging, caloric restriction, or physical exercise, readily alter the activity of sirtuins. The exercise-induced adaptive response, which includes metabolic and redox processes, involves the sirtuin protein family. NAD, nicotinamide adenine dinucleotide. (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)

FIG. 9.

The suggested mechanisms between acetylation, protein stability, aging, and cellular function. Lysine acetylation could prevent the ubiquitination of the same lysine residue, and hence effect protein stability and half-life. Longer half-life results in significantly increased carbonylation of protein residues, which results in impaired cellular function.

FIG. 10.

Exercise results in large metabolic challenges to skeletal muscle that cause mitochondrial biogenesis and alteration of the mitochondrial network affecting fusion and fission. ROS are important signaling molecules for muscle contractions, PGC-1α, MAPK, as well as for transcription factor NF-κB. NAD⁺/NADH levels are readily modified by ROS and could affect the activity of sirtuins (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.) AP-1, activator protein-1; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; Mn-SOD, manganese superoxide dismutase; NF-κB, nuclear factor-kappaB; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator 1α.

FIG. 11.

The function-promoting effects of regular exercise on different cellular functions include the upregulation of antioxidant, oxidative damage-repairing systems, neurogenesis, and induction of trophic factors. (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.) BDNF, brain-derived neurotrophic factor.

FIG. 12.

Exercise results in enhanced ROS production, which activates the p38γ MAPK, AMPK, and HIF1α pathways leading to mitochondrial biogenesis and angiogenesis that are an important part of exercise-induced adaptation. AMPK, AMP-activated protein kinase; HIF-1α, hypoxia-inducible factor-1a; VEGF, vascular endothelial growth factor.

FIG. 13.

Exercise induces marked release of Ca²⁺ from the sarcoplasmic reticulum, which binds to troponin to allow the generation of cross bridges between myosin and actin filaments. Moreover, it activates calmodulin-dependent protein kinase (CaMK) that could lead to enhanced expression of GLUT4 glucose transporter. Then, as a result of insulin-mediated signaling, more GLUT4 can translocate to the membranes leading to increased glucose uptake by skeletal muscle. CaMK can also activate increased capillarization via VEGF. PPAR, peroxisome proliferator-activated receptor. (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)

FIG. 14.

Oxygen sensing and angiogenesis are dependent on the HIF-1-VEGF axis, which is mediated by hydrogen peroxide-dependent signaling. The figure shows some of the key elements of the suggested signaling pathways (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.) Akt, protein kinase B; ERK, extracellular signal-regulated kinase; PI3-K, phosphatidylinositol 3-kinase.

FIG. 15.

Tight heterochromatin suppresses the rate of transcriptions, while euchromatin allows rapid response to challenges by gene transcription. The tightness of chromatin is dependent on post-translational modification of histone residues. The suggested mechanism by which exercise could play a role in DNA methylation and post-translational modifications of histone residues. Histone acetyl transferases and deacetylases, such as p300/CBP and SIRT1, are readily modified by exercise and aging, which might affect epigenetics. Exercise increases DNA methylation at the BDNF gene promoter region and also increases the acetylation of H3, and these modifications result in enhanced production of BDNF in the hippocampus (To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.) CR, caloric restriction; HAT, histone acetyl transferases.