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EDITORIAL
HIGHLIGHTED TOPIC
Free Radical Biology in Skeletal Muscle
How times have changed! Since the mid-’90s, biologists have established that free radicals—reactive oxygen species (ROS), nitric oxide (NO), and their derivatives—are constitutive elements of the physiological milieu in virtually all eukaryotic cells types, including skeletal muscle. Reflecting this reality, the Journal has published an average of three original reports on free radical biology per issue over the last decade. These manuscripts have included landmark reports on free radical production by skeletal muscle, on antioxidants that buffer oxidant activity in muscle cells, and on aspects of muscle function that are modulated by ROS and NO derivatives.
The current Highlighted Topic series provides a forum for collected publication of the latest discoveries about oxidant activity in muscle. Original reports from laboratories in North America and abroad reflect the current frontiers of knowledge in this field, both conceptually and technically. These original articles illustrate the exciting advances being made in redox biology and reinforce the commitment to innovative science that now typifies the Journal. This series also includes invited mini-reviews on distinct aspects of redox biology in skeletal muscle. We are privileged to have articles written by established investigators, scientists who have contributed importantly to the field and understand the issues first hand. Written in a style that is integrative and accessible, these articles provide the nonspecialist with valuable overviews of each individual topic.
Among our mini-reviews, oxidant production by skeletal muscle may be the most fundamental topic. Dr. Jackson and associates (2) have taken a comprehensive approach to this subject, integrating the published information on both ROS and NO production. This article provides perspective on the contributions of various intracellular sources and the identity of oxidants produced by muscle. The authors also review our knowledge of oxidant distribution within muscle tissue, discriminating among compartments that may influence the biological activity of muscle-derived ROS and NO. This lays the groundwork for other mini-reviews that address oxidant effects on muscle structure and function.
Glucose uptake is clearly sensitive to muscle-derived oxidants. This is best described for NO, which appears to promote glucose uptake during muscle contraction, a property reviewed in the Journal last year (3). The potential role of muscle-derived ROS is less widely appreciated. Muscle clearly generates increased amounts of ROS and takes up additional glucose during repetitive contraction. Hydrogen peroxide and other ROS are known to stimulate glucose uptake by muscle. The obvious question is whether muscle-derived ROS drive the increase in glucose uptake that occurs during contraction? Dr. Katz (4) has reviewed this emerging story, succinctly providing background on the converging lines of research that support this hypothesis and laying out new data that begin to test the question directly.
Skeletal muscle routinely experiences hypoxia under physiological conditions, e.g., strenuous exercise and high altitude. In turn, hypoxia alters gene expression in muscle and can compromise both metabolic and contractile function. The available evidence suggests that hypoxia-induced oxidants contribute importantly to these responses. The mini-review by Dr. Clanton (1) outlines the physiological importance of hypoxia in skeletal muscle, describes the impact of hypoxia on oxidant production in muscle, and reviews the data that suggest that oxidants mediate hypoxia effects.
For over a decade, muscle-derived oxidants have been implicated as mediators of skeletal muscle wasting and weakness caused by limb restriction or mechanical unloading. Dr. Powers and associates (5) provide an overview of this literature, integrating the data from limb muscle and respiratory muscle that suggest a redox mechanism. This article reviews the evidence that oxidant activity is increased by prolonged unloading and that unloaded muscle experiences oxidative stress. More importantly, the published data make a convincing case for causality. The literature shows that loss of muscle mass and muscle function can be blunted by buffering oxidants via antioxidant administration.
Oxidants also play a role in muscle inflammation. During strenuous exercise, limb and respiratory skeletal muscles generate an array of proinflammatory biomolecules that includes ROS, NO, and cytokines. Drs. Vassilakopoulos and Hussain (8) have described this response in some detail, placing a special emphasis on oxidant and cytokine production by the respiratory muscles. Their article also reviews the influence of muscle-derived cytokines and oxidants on the muscle, an autocrine/paracrine action that influences contractile function and cellular adaptation.
In contrast, Drs. Supinski and Callahan (6) have considered the response to circulating cytokines generated by a remote source. This mini-review has a more pathophysiological focus, addressing the cellular and molecular mechanisms responsible for atrophy and contractile dysfunction during chronic systemic inflammation. The data in this well-established field are extensive and compelling. The authors leave little doubt that cytokine-stimulated oxidants may be central mediators of muscle weakness caused by chronic inflammation.
Finally, the pathophysiology of genetic muscle diseases can also have a strong redox component. The mini-review by Drs. Tidball and Wehling-Henricks (7) illustrates this point by addressing the role of free radicals in muscular dystrophy. This is a complex and fascinating tale linked to dysregulation of both NO and ROS within dystrophic muscle fibers. The functional outcome can be catastrophic and, again, free radicals appear to play a causal role.
Taken together, the articles in this Highlighted Topics series are exciting. The mini-reviews are highly informative: authoritative and erudite overviews of the biological roles that oxidants play in skeletal muscle. The original reports bring diversity and immediacy to the series, providing new evidence of how and where free radicals are important in muscle. I applaud the accomplishments of our many contributing authors and urge you to join me in reading the thought-provoking articles in this series.
Department of Physiology
University of Kentucky
Lexington, Kentucky
e-mail: michael.reid{at}uky.edu
REFERENCES
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  A. R. Tupling, C. Vigna, R. J. Ford, S. C. Tsuchiya, D. A. Graham, S. G. Denniss, and J. W. E. Rush Effects of buthionine sulfoximine treatment on diaphragm contractility and SR Ca2+ pump function in rats J Appl Physiol, December 1, 2007; 103(6): 1921 - 1928. [Abstract] [Full Text] [PDF]
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