Effects of Exercise-Induced ROS on the Pathophysiological Functions of Skeletal Muscle

Abstract

Oxidative stress is the imbalance of the redox system in the body, which produces excessive reactive oxygen species, leads to multiple cellular damages, and closely relates to some pathological conditions, such as insulin resistance and inflammation. Meanwhile, exercise as an external stimulus of oxidative stress causes the changes of pathophysiological functions in the tissues and organs, including skeletal muscle. Exercise-induced oxidative stress is considered to have different effects on the structure and function of skeletal muscle. Long-term regular or moderate exercise-induced oxidative stress is closely related to the formation of muscle adaptation, while excessive free radicals produced by strenuous or acute exercise can cause muscle oxidative stress fatigue and damage, which impacts exercise capacity and damages the body’s health. The present review systematically summarizes the relationship between exercise-induced oxidative stress and the adaptions, damage, and fatigue in skeletal muscle, in order to clarify the effects of exercise-induced oxidative stress on the pathophysiological functions of skeletal muscle.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

Exercise as a common stressor leads to oxygen supply that cannot meet a rapid increase in oxygen demand of the body; then, many tissues and organs produce some highly active molecules, such as reactive nitrogen species (RNS) and reactive oxygen species (ROS). ROS plays a pivotal role in the stress process, including superoxide anion (O₂^⋅-), hydroxyl radical (OH^⋅-), and hydrogen peroxide (H₂O₂) (Figure 1) [1]. The production of ROS exceeds its scavenging capacity, which is the reaction of oxidative stress. Under normal physiological conditions, ROS participates in a number of cell activities, including cell energy metabolism, signal transduction, and gene expression regulation, but high levels of ROS can also damage biomacromolecules in cells, such as lipids, proteins, and nucleic acids, leading to cell senescence even death [2]. A large number of studies have shown that regular or suitable exercise produces low-level ROS, while excessive production of endogenous free radicals during exercise can damage the physiological functions of the entire tissue [1–3], such as skeletal muscle [3]. Skeletal muscle is the dynamic part of the exercise system, and the physiological level ROS is an essential substance for maintaining its function, which is involved in the production of muscle force, the maintenance of muscle content, intracellular signal transduction, gene expression, and other related activities, while excessive ROS causes the dysfunction of contraction and muscle weakness [4]. As is well known, ROS induced by skeletal muscle contraction during exercise can increase the level of oxidative stress and enhance the antioxidant defense system. Although exercise-induced reactive oxygen species are required for normal force production in skeletal muscle, the high levels of ROS can contribute to contractile dysfunction [5]. The sarcoplasmic reticulum Ca²⁺ release channel is highly sensitive to ROS, which will reduce the sensitivity of myofibrils to Ca²⁺ and then affect muscle contraction [5, 6]. In addition, the accumulation of ROS in the body depends on exercise mode, exercise intensity, and duration. Therefore, exercise-induced oxidative stress may play an important role in the pathophysiological functions of skeletal muscle.

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Moreover, exercise-activated Nrf2 may regulate skeletal muscle mitochondria by promoting mitochondrial biogenesis, improving mitochondrial respiratory function, and regulating mitochondrial autophagy. In addition, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) plays an important role in glucose uptake, mitochondriogenesis, and hypertrophy in skeletal muscle responses to physical exercise [24]. Exercise-induced ROS can couple with lactate metabolism to stimulate PGC-1α production, especially endurance exercise [24]. PGC-1α coactivates nuclear respiratory factor- (NRF-) 1 and NRF-2 to increase their DNA binding in skeletal muscle after acute exercise [24], then activates the genes encoding COX and mitochondrial transcription factor A (TFAM), which activate mitochondrial DNA transcription, thereby increasing mitochondrial synthesis [24]. In addition, exercise-induced ROS are able to stimulate the skeletal muscle to secrete myokines, which also play important roles in the regulation of cell signaling and muscle metabolic adaptation [27, 28], such as interleukin-15 (IL-15). IL-15 is a regulator to control intracellular ROS production and attenuate oxidative stress in skeletal muscle cells [29].

5. Skeletal Muscle Cell Damage

Exhaustive exercise can increase the peroxidation and weaken the antioxidant capacity in skeletal muscles, which can cause the damage of skeletal muscle cells through modification of lipid, protein, and DNA.

Firstly, for lipid damage, biomembrane is the main component of cells. Lipid peroxidation caused by excessive endogenous ROS during exercise can change the liquidity, fluidity, and permeability of the biomembrane, which in turn leads to membrane dysfunction [30]. The lipid bilayer contains a large amount of polyunsaturated fatty acid (PUFA). ROS can deprive the hydrogen at the diallyl position in PUFA to form unsaturated fatty acid free radicals, then combine with oxygen molecules to generate lipid peroxyl radicals LOO^⋅- [31]. LOO^⋅- can deprive the allyl groups of unsaturated fatty acid hydrogen which forms a new unsaturated fatty acid free radical and lipid peroxide (LOOH), causing oxidative damage to the biomembranes of skeletal muscle cells [31].

Secondly, for protein damage, ROS plays a very important role in the process of protein metabolism, which can promote protein turnover and renewal under physiological conditions. But excessive ROS induced by exercise will cause damage to proteins and induce the inactivation of enzymes, the loss of receptors, and the decline of immune function [31]. The damage of proteins by ROS is mainly to change their activities. OH^⋅- can change the primary structure of the protein and contribute to the secondary and tertiary structure modification, so that the polypeptide chain unfolds to form a random structure [32]. These modifications expose the originally shielded peptide bonds to proteolytic enzymes. In addition, a protein is combined with OH^⋅- which will increase the production of double tyrosine, further induce the breakage, which is manifested by the effect of extracting hydrogen on the a-carbon atom of the amino acid, and then react with O₂^⋅- to generate LOO^-, ultimately forming peroxides [32].

The last is DNA damage. 8-Hydroxydeoxyguanosine (8-OHdG) is an important marker for the detection of oxidative DNA damage. The C-8 position of the base guanine in the DNA chain is susceptible to the attack of OH^⋅- and O₂^⋅- and undergoes hydroxylation to form the adduct 8-OHdG [33]. OH^- combines with the deoxyguanine nucleotide residues at the C-4, C-5, or C-8 positions of DNA bases to form 8-hydroxy-7,8-dihydroxyguanine nucleotides, which in turn further oxidizes to generate 8-hydroxydeoxyguanine nucleotides. Simultaneously, during the replication process, 8-OHdG on the DNA chain can pair with other bases than C to form point mutations, such as GC→TA [32].

6. Skeletal Muscle Fatigue

The process of sports fatigue is a complex physiological phenomenon; it actually occurs with the consumption of physical energy or the accumulation of metabolites, including skeletal muscle fatigue, visceral fatigue, and nerve fatigue. Skeletal muscle fatigue is the main peripheral manifestation of sports fatigue. The production of skeletal muscle strength depends on its contraction mechanisms, while any disorder of the nerves, ions, blood vessels, and energy systems upstream of the cross bridge will lead to their loss and cause muscle fatigue, especially the energy metabolism factors during the process of muscle contraction, such as H⁺, lactic acid, Pi, reactive ROS, heat shock protein (HSP), α-acid glycoprotein (ORM) which also affect muscle fatigue.

Excessive ROS produced by strenuous exercise may cause exercise fatigue by reducing the release of skeletal muscle sarcoplasmic reticulum Ca²⁺ and/or the sensitivity of myofibrils Ca²⁺ [34]. However, under mild oxidative stress induced by physical exercise, the S-glutathionization of troponin can improve contractile apparatus Ca²⁺ sensitivity in fast-twitch fibers, thereby delaying the occurrence of fatigue [35]. However, antioxidants restored Ca²⁺ to release in the sarcoplasmic reticulum, but the decrease in muscle strength during fatigue cannot be eliminated [36], indicating that oxidative stress caused by exercise is closely related to muscle fatigue. Endogenous and exogenous ROS not only may hinder muscle fiber contraction by affecting the release and uptake of Ca²⁺ in the sarcoplasmic reticulum and reducing the activity of troponin but also can promote the occurrence of exercise fatigue by destroying mitochondrial functions and inhibiting aerobic metabolism [6]. In addition, during exercise, the increased energy metabolism rate leads to excessive mitochondrial ROS production in fatigued skeletal muscle cells, which further leads to the occurrence of the oxidative modification of lipids, proteins, and DNA.

7. Conclusion

Together, exercise-induced oxidative stress has dual effects on skeletal muscle tissue. Proper exercise can promote generation of the physiological levels of ROS, maintain the normal skeletal muscle function, and facilitate exercise adaptation, while exhaustive exercise can cause the body to produce too much ROS, which causes excessive oxidative stress, leading to fatigue and cell damage of skeletal muscle. Therefore, further understanding the effect of exercise-induced oxidative stress on the pathophysiological functions of skeletal muscle is very important for guiding exercise to promote health and provides a direction to explore the molecular mechanism of exercise to improve the development of pathophysiological processes in oxidative stress-related diseases.

Authors’ Contributions

The work was conceived by FW, XW, YL, and ZZ; draft writing was performed by FW and XW; and the manuscript was revised by YL and ZZ. All authors reviewed and approved the final version of the manuscript for publication.

Acknowledgments

This work was supported by the Key Projects of Scientific and Technological Innovation in Fujian Province (2021G02021 and 2021G02023), Special Funds of the Central Government Guilding Local Science and Technology Development (2020L3008), Fujian Provincial Natural Science Foundation (2019R1011-3 and 2020J01176), and Scientific Research Talent Project of Fujian Provincial Health Commission (2018-ZQN-20).

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