Hindawi Publishing Corporation Journal of Signal Transduction Volume 2012, Article ID 982794, 17 pages doi:10.1155/2012/982794 Review Article Reactive Oxygen Species in Skeletal Muscle Signaling Elena Barbieri and Piero Sestili Dipartimento di Scienze Biomolecolari, Universita` degli Studi di Urbino “Carlo Bo”, via Saﬃ 2, 61029 Urbino, Italy Correspondence should be addressed to Piero Sestili, piero.sestili@uniurb.it Received 30 June 2011; Accepted 25 August 2011 Academic Editor: Saverio Francesco Retta Copyright © 2012 E. Barbieri and P. Sestili. 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. Generation of reactive oxygen species (ROS) is a ubiquitous phenomenon in eukaryotic cells’ life. Up to the 1990s of the past century, ROS have been solely considered as toxic species resulting in oxidative stress, pathogenesis and aging. However, there is now clear evidence that ROS are not merely toxic species but also—within certain concentrations—useful signaling molecules regulating physiological processes. During intense skeletal muscle contractile activity myotubes’ mitochondria generate high ROS ﬂows: this renders skeletal muscle a tissue where ROS hold a particular relevance. According to their hormetic nature, in muscles ROS may trigger diﬀerent signaling pathways leading to diverging responses, from adaptation to cell death. Whether a “positive” or “negative” response will prevail depends on many variables such as, among others, the site of ROS production, the persistence of ROS ﬂow or target cells’ antioxidant status. In this light, a speciﬁc threshold of physiological ROS concentrations above which ROS exert negative, toxic eﬀects is hard to determine, and the concept of “physiologically compatible” levels of ROS would better ﬁt with such a dynamic scenario. In this review these concepts will be discussed along with the most relevant signaling pathways triggered and/or aﬀected by ROS in skeletal muscle. 1. Introduction Oxidative stressors, such as reactive oxygen species (ROS), have been initially and long considered as merely delete- rious species to skeletal muscle tissue. Indeed, since the 1980s abundant evidence clearly indicated that ROS play a pathogenic role in inherited muscular dystrophies [1] and have then been identiﬁed as concausal factors in various muscular diseases [2–5]. However, and thereafter, accumulating evidence indicated that ROS, at least within concentrations emerging from physiological conditions, could also play a positive role in physiologically relevant processes in muscle cells. As an example, inﬂammation- derived ROS play a contradictory role in muscle repair [2]: in combination with other actors such as growth factors and chemokines, ROS participate in a cascade of events leading to muscle regeneration and repair; on the contrary, the local persistence of ROS sustained by inﬁltrated neu- trophils may cause further injury by oxidatively damaging diﬀerentiating myoblasts and myotubes thus delaying the restitutio ad integrum. Similarly, ROS generated during exercise promote mitochondriogenesis (a key factor in mus- cle diﬀerentiation) via peroxisome proliferator-activated- receptor-gamma-coactivator-1α-(PGC-1α) activated signal transduction pathway [3] but, at higher and persistent levels, they might target mitochondria and mitochondrial DNA (mtDNA) turning into blockers of myogenic diﬀerentiation [4, 5]. Other examples of such diverging capacities—which strengthen the generally accepted notion that ROS act in a hormetic fashion—will be discussed thereafter. The prevalence of each of the two actions, that is, beneﬁcial or detrimental, depends on the coincidence of various intrinsic and extrinsic factors among which the most prominent is the level and the duration of ROS targeting muscle cells; other variables are the source or the site of ROS generation, the antioxidant status of target cells, and their DNA repair capacity. The diﬀerentiation stage of muscle cells (satellite cell, diﬀerentiating myoblast or mature myotube) is also capable of redirecting the cell through diﬀerent signaling pathways and of further modulating the ensuing cell response. Today ROS are known to trigger and/or aﬀect many signaling pathways relevant to skeletal muscle cells’