Exercise-induced skeletal muscle signaling pathways and human athletic performance Donny M. Camera a , William J. Smiles a , John A. Hawley a,b,n a Centre for Exercise and Nutrition, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Vic. 3065, Australia b Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom article info Article history: Received 9 November 2015 Received in revised form 28 January 2016 Accepted 3 February 2016 Available online 11 February 2016 Keywords: Endurance exercise Resistance exercise Cell signaling Molecular adaptation responses Responder abstract Skeletal muscle is a highly malleable tissue capable of altering its phenotype in response to external stimuli including exercise. This response is determined by the mode, (endurance- versus resistance- based), volume, intensity and frequency of exercise performed with the magnitude of this response- adaptation the basis for enhanced physical work capacity. However, training-induced adaptations in skeletal muscle are variable and unpredictable between individuals. With the recent application of molecular techniques to exercise biology, there has been a greater understanding of the multiplicity and complexity of cellular networks involved in exercise responses. This review summarizes the molecular and cellular events mediating adaptation processes in skeletal muscle in response to exercise. We discuss established and novel cell signaling proteins mediating key physiological responses associated with enhanced exercise performance and the capacity for reactive oxygen and nitrogen species to modulate training adaptation responses. We also examine the molecular bases underpinning heterogeneous re- sponses to resistance and endurance exercise and the dissociation between molecular ‘markers’ of training adaptation and subsequent exercise performance. & 2016 Elsevier Inc. All rights reserved. 1. Introduction The conversion of multiple signals generated during exercise to molecular events aimed at conserving cellular homeostasis and ultimately inducing phenotypic changes in skeletal muscle in- volves a cascade of events resulting in the activation and/or re- pression of specific signaling pathways regulating gene expression and protein synthesis/degradation [1–4]. One exercise-induced perturbation to cellular homeostasis is the increase in reactive oxygen (ROS) and nitrogen (RNS) species [5]. The generation of ROS and RNS products by the mitochondria and other subcellular compartments with exercise induce cellular damage and activates redox signaling pathways that can modulate the molecular me- chanisms regulating protein synthesis and breakdown processes that ultimately form the basis for exercise training adaptations [5,6]. An important concept developed over the past decade is that the chronic responses to exercise training are likely to be the result of the acute, but cumulative effects of the responses to single ex- ercise bouts [7]. As such, these acute and transient changes in gene transcription following a single exercise bout, when reinforced by repeated exercise stimuli, result in chronic effects on the rates of protein breakdown/synthesis that ultimately form the basis of skeletal muscle training adaptation and improvements in exercise capacity/performance [2,8]. Yet despite major breakthroughs in our understanding of how different exercise modalities activate specific cellular, molecular, and biochemical pathways, our un- derstanding of how these effects exert their performance-enhan- cing benefit remains elusive. This is, perhaps, not surprising, given that exercise performance on any given day is ultimately the result of integrating multiple physiological, biomechanical and psycho- logical factors simultaneously under a variety of different en- vironmental conditions. Indeed, some of the variability observed in the physiological responses to standardized training protocols is likely to be underpinned by the multi-factorial and complex nat- ure of the ‘exercise response.’ In this review we examine the molecular basis for exercise training-induced adaptations in ske- letal muscle in response to both resistance- and endurance-based exercise including the roles of ROS and RNS on these cellular processes. We also examine the molecular bases underpinning these adaptations that may help explain the heterogeneous re- sponses to exercise training, and the apparent dissociation be- tween molecular ‘markers’ of training adaptation and subsequent exercise performance. The reader is also referred to several recent reviews published on these topics [2,3,9]. Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/freeradbiomed Free Radical Biology and Medicine http://dx.doi.org/10.1016/j.freeradbiomed.2016.02.007 0891-5849/& 2016 Elsevier Inc. All rights reserved. n Corresponding author at: Centre for Exercise and Nutrition, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Vic. 3065, Australia. E-mail address: john.hawley@acu.edu.au (J.A. Hawley). Free Radical Biology and Medicine 98 (2016) 131–143