Free radicals and muscle fatigue: Of ROS, canaries, and the IOC

doi:10.1016/j.freeradbiomed.2007.03.002

Free Radical Biology and Medicine

Volume 44, Issue 2, 15 January 2008, Pages 169-179

https://doi.org/10.1016/j.freeradbiomed.2007.03.002 Get rights and content

Abstract

Skeletal muscle fibers continually generate reactive oxygen species (ROS) at a slow rate that increases during muscle contraction. This activity-dependent increase in ROS production contributes to fatigue of skeletal muscle during strenuous exercise. Existing data suggest that muscle-derived ROS primarily act on myofibrillar proteins to inhibit calcium sensitivity and depress force. Decrements in calcium sensitivity and force are acutely reversible by dithiothreitol, a thiol-selective reducing agent. These observations suggest that thiol modifications on one or more regulatory proteins are responsible for oxidant-induced losses during fatigue. More intense ROS exposure leads to losses in calcium regulation that mimic pathologic changes and are not reversible. Studies in humans, quadrupeds, and isolated muscle preparations indicate that antioxidant pretreatment can delay muscle fatigue. In humans, this phenomenon is best defined for N-acetylcysteine (NAC), a reduced thiol donor that supports glutathione resynthesis. NAC has been shown to inhibit fatigue in healthy adults during electrical muscle activation, inspiratory resistive loading, handgrip exercise, and intense cycling. These findings identify ROS as endogenous mediators of muscle fatigue and highlight the importance of future research to (a) define the cellular mechanism of ROS action and (b) develop antioxidants as novel therapeutic interventions for treating fatigue.

Section snippets

Beginnings of the field

Strenuous exercise increases free radical content in skeletal muscle. This phenomenon became widely appreciated after Davies and co-workers [1] used electron paramagnetic resonance spectroscopy to measure carbon-based radicals in rabbit muscle before and after exhaustive exercise. Jackson and associates [2] subsequently extended this observation to humans, using electron spin resonance to demonstrate increased free radicals in limb muscle after exercise. These findings were soon complemented by

Muscle-derived oxidants

The focus was now muscle biology. Research determined that skeletal muscle produces reactive oxygen species (ROS)—including superoxide anions [33], [35], [36], [37], [38], [39], hydrogen peroxide [33], [37], and hydroxyl radicals [37], [38], [40], [41], [42]—in the absence of disease. Fig. 2 illustrates early evidence of ROS production by muscle. Subsequent research has detected ROS in the cytosol of intact fibers [33], [39], [43], in the extracellular compartment [35], [37], [38], [44], [45],

The intact fiber preparation

Intact muscle fibers are a unique tool for testing fatigue mechanisms at the cellular level. Intact fibers retain the entire complement of oxidant sources, antioxidant buffers, and redox-sensitive target molecules that may influence fatigue in vivo. Environmental conditions that affect redox state, e.g., frequency and intensity of contractions, temperature, oxygen tension, CO₂ tension, and pH, can be tightly regulated. And it is possible to simultaneously monitor changes in force production and

Feasibility of performance enhancement

We now know that muscle-derived oxidants play a causal role in fatigue. It is also clear that antioxidant probes can interrupt this link, lessening oxidant activity and increasing mechanical performance in the laboratory. Thus, it is logical that physicians, scientists, and perhaps the International Olympic Committee (IOC) might ask if antioxidants can enhance human performance.

The answer has been slow to evolve. Most early studies tested the effects of nutritional antioxidants. Volunteers

Summary and conclusions

A quarter-century of research has established that muscle-derived free radicals, probably ROS, play a causal role in fatigue. Oxidants seem to depress force by decreasing myofibrillar calcium sensitivity, either directly or indirectly. The molecular target of ROS action remains undefined and is a promising focus for future research. The field would benefit from systematic analyses of relevant proteins: troponin, tropomyosin, myosin heavy and light chains, and the actin active site. The

Acknowledgments

Our research in this field is supported by the National Space Biomedical Research Institute through NASA NCC 9-58 and by National Institutes of Health Grant HL45721.

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Review ArticleFree radicals and muscle fatigue: Of ROS, canaries, and the IOC

Abstract

Section snippets

Beginnings of the field

Muscle-derived oxidants

The intact fiber preparation

Feasibility of performance enhancement

Summary and conclusions

Acknowledgments

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Acta

FEBS Lett.

Arch. Biochem. Biophys.

FEBS Lett.

Pharmacol. Res.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Am. J. Pathol.

Free Radic. Biol. Med.

Mech. Ageing Dev.

J. Biol. Chem.

Cell Signalling

Arch. Biochem. Biophys.

Free Radic. Biol. Med.

Oxidants and antioxidants in exercise

J. Appl. Physiol.

Exercise-induced oxidative stress

Med. Sci. Sports Exerc.

Skeletal muscle and liver glutathione homeostasis in response to training, exercise, and immobilization

J. Appl. Physiol.

Oxypurinol administration fails to prevent free radical-mediated lipid peroxidation during loaded breathing

J. Appl. Physiol.

Exercise-induced lipid peroxidation and leakage of enzymes before and after vitamin E supplementation

Int. J. Biochem.

Protein carbonyl formation in the diaphragm

Am. J. Respir. Cell Mol. Biol.

Exercise-induced metallothionein expression in human skeletal muscle fibres

Exp. Physiol.

Regulation of nitric oxide production in limb and ventilatory muscles during chronic exercise training

Am. J. Physiol. Lung Cell Mol. Physiol.

The effects of moderate, strenuous, and overtraining on oxidative stress markers and DNA damage in rat liver

Can. J. Appl. Physiol.

Evaluation of a multi-parameter biomarker set for oxidative damage in man: increased urinary excretion of lipid, protein, and DNA oxidation products after one hour of exercise

Free Radic. Res.

Pharmacological study on Agkistrodon blomhoffii blomhoffii BOIE.V. anti-fatigue effect of the 50% ethanol extract in acute weight-loaded forced swimming-treated rats

Biol. Pharm. Bull.

Nutritional antioxidants as therapeutic and preventive modalities in exercise-induced muscle damage

Can. J. Appl. Physiol.

Free radicals, exercise and antioxidant supplementation

Proc. Nutr. Soc.

Oxidants, antioxidant nutrients, and the athlete

J. Sports Sci.

Diaphragmatic fatigue in man

J. Appl. Physiol.

Respiratory muscle fatigue: report of the Respiratory Muscle Fatigue Workshop Group

Am. Rev. Respir. Dis.

Structure and function of the respiratory muscles in patients with COPD: impairment or adaptation

Eur. Respir. J. Suppl.

Peripheral and respiratory muscles in chronic heart failure

Eur. Respir. J.

Diaphragmatic fatigue during sepsis and septic shock

Intensive Care Med.

Pharmacologic enhancement of respiratory muscle function

Semin. Respir. Med.

Effect of N-acetylcysteine on diaphragm fatigue

J. Appl. Physiol.

GSH rescue by N-acetylcysteine

Klin. Wochenschr.

Spinal and supraspinal factors in human muscle fatigue

Physiol. Rev.

N-acetylcysteine depresses contractility and inhibits fatigue of diaphragm in vitro

J. Appl. Physiol.

Reactive oxygen in skeletal muscle. I. Intracellular oxidant kinetics and fatigue in vitro

J. Appl. Physiol.

Fatigue-sparing effects of acetylcysteine on the diaphragm are temperature-dependent

Review Article
Free radicals and muscle fatigue: Of ROS, canaries, and the IOC