Mitochondria in the middle: exercise preconditioning protection of striated muscle.

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Mitochondria in the middle: exercise preconditioning protection of striated muscle John M. Lawler, Dinah A. Rodriguez and Jeffrey M. Hord Redox Biology & Cell Signalling Laboratory, Department of Health and Kinesiology, Graduate Faculty of Nutrition & Food Science, Texas A&M University, College Station, TX, USA Sarcolemma

Nox

The Journal of Physiology

NF-κB ROS

XO

δ-Opioid receptor

Exercise preconditioning (EPC)

Gene expression HIF-1, Nrf2, etc. Nucleus

Post-translational modifications

• Cytosolic antioxidants • Heat shock proteins • Nitric oxide signaling

Mitochondrial adaptations: • MnSOD • Trx2 • ICDH-NADP • mitoKATP channels • HSP70 • SIRT-1/PGC-1α

MAPK

Mitochondria Blood vessel

Abstract Cellular and physiological adaptations to an atmosphere which became enriched in molecular oxygen spurred the development of a layered system of stress protection, including antioxidant and stress response proteins. At physiological levels reactive oxygen and nitrogen species regulate cell signalling as well as intracellular and intercellular communication. Exercise and physical activity confer a variety of stressors on skeletal muscle and the cardiovascular system: mechanical, metabolic, oxidative. Transient increases of stressors during acute bouts of

Dinah A. Rodriguez, John M. Lawler, and Jeffrey M. Hord work in the Department of Health and Kinesiology at Texas A&M University (USA). John Lawler is a Professor in the Department of Health and Kinesiology and Director of the Redox Biology & Cell Signaling Laboratory, and leads the research group on projects focusing on the production of reactive oxygen species (ROS) and the resulting ROS-related cellular signalling pathways in striated muscle. Dinah Rodriguez is currently a Masters student. Jeffrey Hord is currently a Doctoral candidate whose research has primarily focused on understanding the redox-sensitive cell signalling pathways involved in disuse-induced skeletal muscle atrophy.

C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society

DOI: 10.1113/JP270656

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exercise or exercise training stimulate enhancement of cellular stress protection against future insults of oxidative, metabolic and mechanical stressors that could induce injury or disease. This phenomenon has been termed both hormesis and exercise preconditioning (EPC). EPC stimulates transcription factors such as Nrf-1 and heat shock factor-1 and up-regulates gene expression of a cadre of cytosolic (e.g. glutathione peroxidase and heat shock proteins) and mitochondrial adaptive or stress proteins (e.g. manganese superoxide dismutase, mitochondrial KATP channels and peroxisome proliferator activated receptor γ coactivator-1 (PGC-1)). Stress response and antioxidant enzyme inducibility with exercise lead to protection against striated muscle damage, oxidative stress and injury. EPC may indeed provide significant clinical protection against ischaemia–reperfusion injury, Type II diabetes and ageing. New molecular mechanisms of protection, such as δ-opioid receptor regulation and mitophagy, reinforce the notion that mitochondrial adaptations (e.g. heat shock proteins, antioxidant enzymes and sirtuin-1/PGC-1 signalling) are central to the protective effects of exercise preconditioning. (Received 29 September 2015; accepted after revision 1 April 2016; first published online 6 April 2016) Corresponding author J. M. Lawler: 213A Heldenfels Hall, Department of Health and Kinesiology, Graduate Faculty of Nutrition, Texas A&M University, College Station, TX 77843-4243, USA. Email: [email protected] Abstract figure legend Mild, non-exhaustive exercise results in a rise in reactive oxygen species (ROS) that leads to cellular adaptations capable of offering defence against ischemia–reperfusion (I/R) injury in striated muscle fibres. These exercise-induced cardiac and skeletal muscle adaptations are referred to as exercise preconditioning (EPC). EPC induces ROS production from mitochondria, NADPH oxidase (Nox) and xanthine oxidase (XO). The ROS produced from these oxidant sources leads to increased expression and post-translational modifications of cytosolic antioxidants and cytosolic HSPs, and enhanced nitric oxide signalling. Mitochondrial adaptations such as increased MnSOD, Trx2, NADP-specific isocitrate dehydrogenase (ICDH-NADP), mitochdonrial KATP (mitoKATP ) channels, HSP70 and SIRT-1/PGC-1α are also outcomes of EPC. Another potential limb of EPC involves mitochondrial adaptations being driven by δ-opiod receptor activation and subsequent P38/MAPK signalling. Abbreviations AMPK, adenosine monophosphate kinase; BNIP3, Bcl2/adenovirus E1B 19 kDa interacting protein 3; Cu/ZnSOD, copper/zinc superoxide dismutase; EC-SOD, extracellular superoxide dismutase; EPC, exercise preconditioning; ETC, electron transport chain; FoxO3a, forkhead box O3a; GAS, general adaptation syndrome; GPX, glutathione peroxidase; GSH, reduced glutathione; GSSG, glutathione disulfide; HSF-1, heat shock factor-1; HSP, heat shock protein; I-κB, inhibitor of kappa B; IPC, ischemic preconditioning; I/R, ischaemia–reperfusion; KATP , ATP-sensitive K+ channel; LC3, microtubule associated protein light chain 3; MAPK, mitogen-activated protein kinases; mdx, mouse model of Duchenne/Becker muscular dystrophy; mitoKATP , mitochondrial ATP-sensitive K+ channel; MnSOD, manganese superoxide dismutase; NF-κB, nuclear factor kappa B; Nox, nicotinamide adenine dinucleotide phosphate oxidase; Nrf, nuclear factor-erythroid-2 p45-related factor; PGC-1, peroxisome proliferator activated receptor γ coactivator-1; PKC, protein kinase C; ROS, reactive oxygen species; sarcKATP , sarcolemmal ATP-sensitive K+ channel; SERCA, sarco/endoplasmic reticulum calcium ATPase; SIRT, sirtuin; SOD, superoxide dismutase; TGF-β, transforming growth factor beta; TLR-4, toll-like receptor 4; TNF-α, tumor necrosis factor-alpha; Trx, thioredoxin reductase; VSMC, vascular smooth muscle cell.

Introduction

The general adaptation syndrome (GAS) described the ability of an organism to cope acutely or chronically with dynamic changes in stressors. The general adaptation syndrome was first articulated by Sir Hans Selye (Selye, 1946), an Austrian-Canadian endocrinologist and physician of Hungarian descent, who published over 1700 articles (Neylan, 1998). GAS is a non-specific physiological response that predicts cells, tissues and organisms can experience three stages of response when a stressor is increased: alarm, resistance or adaptation, and exhaustion. While GAS initially pertained to ‘fight or flight’ as well as cortisol effects in patients recovering

from illness or surgery, the theory broadly explains adaptations to environmental stressors (e.g. cold, heat and altitude), changes in mechanical stress and increased metabolic stress. Research over the past 30 years is consistent with the notion that response and adaptations to oxidative stress also follow the tenets of the GAS (de Magalhaes & Church, 2006; Lawler & Hindle, 2011). For example, cells and integrative biological systems respond to moderate redox challenges by increasing antioxidant enzymes and other protective proteins (e.g. heat shock proteins) (Das et al. 1993; Omar & Pappolla, 1993; Radak et al. 2008). A bout of exercise increases mechanical stress, metabolic stress and oxidative stress, which could be injurious at high C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society

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Exercise preconditioning protection of striated muscle

levels of intensity. Thus it is not surprising that levels of many proteins involved in protection against stressors are increased either acutely or as an adaptation to repeated or habitual bouts of exercise in skeletal muscle and the heart (Locke et al. 1995; Samelman, 2000; Khassaf et al. 2001; Kim et al. 2015b). Biological response and adaptations to stressors experienced with exercise provide protection against potential injury or cellular damage in a future bout of exercise or stress. Thus a cellular objective is to maintain homeostasis within a desired cellular and organism tolerance. ‘Preconditioning’ is a term used in biology and physiology to describe a process where small doses of a potential hazardous stimulus, organism, or compound evoke an adaptation and increased resistance to the noxious stimulus. For example, mild ischaemia provokes production of a cluster of stress response proteins (e.g. hypoxia-inducible factor 1a, endothelial nitric oxide synthase, vascular endothelial growth factor, heat shock proteins, manganese superoxide dismutase) that provide protection against damage and cell death (Heads et al. 1995; Hamilton et al. 2003; Starnes et al. 2003). An acute bout of exercise increases skeletal muscle and cardiac levels of reactive oxygen species (ROS) and produces oxidative stress. The term ‘exercise preconditioning’ was first evident in the literature in an article by Radak et al. (2000), where the authors described resistance to oxidative stress in the myocardium induced by exercise training. tert-Butyl hydroperoxide was used as an oxidant challenge over 3 weeks. Exercise training reduced protein carbonyls as a marker of oxidative stress and peptide activity of the proteasome. DT-diaphorase, which maintains coenzyme Q in its reduced or antioxidant state, was increased by exercise and was responsive to tert-butyl hydroperoxide in the exercise group. Exercise preconditioning is now recognized to be critical in not only reducing oxidative stress during exercise, but also mitigating oxidative stress and damage due to ischaemia–reperfusion, reducing glucose intolerance and insulin resistance, as well as attenuating skeletal muscle atrophy (Radak et al. 2000; Ding et al. 2005; Dupont-Versteegden et al. 2006; Fontana et al. 2010). Therefore, the purpose of this review is to examine endogenous antioxidant systems that are (a) inducible with exercise and (b) integral to exercise preconditioning. The review begins with a brief overview of antioxidant enzyme systems and heat shock proteins, and their up-regulation with exercise. The concept of ‘hormesis’ is visited and applied to oxidative stress induction of a signalling cascade with exercise that leads to enhanced stress protection. Exercise preconditioning appears to be a central mechanism for protection against ischaemia–reperfusion, insulin resistance, ageing and mitophagy.


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Antioxidant and stress protection in skeletal muscle and heart

In order to regulate and manage reactive oxygen species and oxidative stress, a posse of antioxidant enzymes evolved when cyanobacteria or blue-green algae released a poisonous gas, oxygen, in runaway quantities into the oceans about 2.3 billion years ago. As oceans released dissolved oxygen into the atmosphere, the proportion of O2 reached levels approached 20% (0.2 atm) about 800 million years ago (Holland, 2006). While oxygen made extinct the vast majority of anaerobic life, high levels of gaseous molecular oxygen (O2 ) allowed, in time, far more complex multicellular organisms to evolve. Tiny creatures that could harness oxygen for energy, which became mitochondria, were incorporated into cells. Utilizing electrons from oxygen for metabolism, organisms adapted to a new environment where cells ‘play with fire,’ and utilize electrons from oxygen for metabolism, movement, cell signalling and tissue remodelling. Single electron reduction of oxygen from O2 yields superoxide anions via a number of cellular sources. Endogenous sources of ROS in striated muscle include the electron transport chain, NADPH oxidases (e.g. Nox2 and Nox4), xanthine oxidase, 5-lipoxygenase, prostaglandin synthesis, peroxisomes and myeloperoxidase. ROS production in striated muscle. The distribution of

ROS, high reactivity, exposure to antioxidant buffering and specificity of sites of production lead to subcellular redox microenvironments. Mitochondria have been long considered a primary cellular source of ROS in striated muscle. Complex I and complex III of the electron transport chain (ETC) can ‘leak’ 1–3% of electron flow through the ETC as superoxide anions (O2 •– ) in the state 4 or resting state (Boveris & Chance, 1973). Because of the high density of protons abutting the inside membrane of the mitochondria, it is nearly impossible for O2 •– to cross through mitochondrial membrane to the cytosol without becoming protonated (Boveris & Chance, 1973). Thus ROS released from mitochondria do so in the form of hydrogen peroxide (H2 O2 ), or peroxynitrite (OONO− ) when superoxide anion reacts with nitric oxide (•NO). In contrast to ETC leakage of ROS in state 3, active contracting skeletal muscle features a far more coupled electronic flux through the ETC, and thus the production of O2 •– dwindles to a stingy leakage of superoxide anions. Increased mitochondrial H2 O2 release during acute exercise was recently linked with forkhead box O3a (FoxO3a) up-regulation (Wang et al. 2015). However, studies from Jackson and colleagues suggest a minor role for mitochondrial ROS when healthy, unfatigued muscle fibres are contracting (Sakellariou et al. 2013, 2014; Claflin et al. 2015).

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However, mitochondrial and microsomal release of ROS become predominant with chronic disease and metabolic disorders (Anderson et al. 2009; Kane et al. 2010; Bikman et al. 2010a; Muoio & Neufer, 2012). Insulin-resistance and Type II diabetes result in a profound release of H2 O2 from mitochondria in animal and human studies (Anderson et al. 2009). In addition, high fat meals result in a large spike of ROS release from both mitochondria and microsomes in skeletal muscle from Zucker rats (Noland et al. 2007). A deluge of lipids from a high fat diet into mitochondria tasks lipid transporters and increases oxidative stress in mitochondria. Microsomes attempt to handle the overflow of lipids, but the consequence is a significant release of ROS (Noland et al. 2007). NADPH oxidase (Nox) is a family of membrane-bound oxidoreductases that produce superoxide anions in response to stretch, contractions, hypoxia, insulin signalling and damage in non-phagocytic and phagocytic cells (Fisher, 2009; Khairallah et al. 2012). The membrane-bound Nox2 isoform of NADPH oxidase responds to stretch and skeletal muscle contractions by releasing ROS (Sakellariou et al. 2014). Jackson and colleagues (Sakellariou et al. 2013) demonstrated, using overexpression of a mitochondria-specific catalase and single fibre experiments, that Nox2 is responsible for most of the ROS released in a stretched or contracting fibre. In healthy, young skeletal muscle, mitochondria appear to contribute little to ROS released during muscle contractions (Sakellariou et al. 2013). Nox2 becomes hyper-responsive to stretch in skeletal muscles of mdx (mouse model of Duchenne/Becker muscular dystrophy) mice, producing excessive ROS (termed ‘X-ROS’) (Prosser et al. 2011; Khairallah et al. 2012). Indeed, Nox2 and X-ROS amplified limb muscle pathology via the stretch-activated Ca2+ channel TRPC1 (transient receptor potential channel 1; Whitehead et al. 2010; Prosser et al. 2011; Khairallah et al. 2012; Kim & Lawler, 2012). Hyper-responsiveness to stretch by Nox2 was dependent upon microtubule conformation (Khairallah et al. 2012) via an unknown mechanism. Hyper-responsiveness of Nox2 to stretch may also be a commonality among limb girdle muscular dystrophies when membrane proteins (e.g. dysferlin) are mutated (Kombairaju et al. 2014). Nox2 also appears hyper-sensitive and up-regulated in skeletal muscle during mechanical unloading (Lawler et al. 2014). However, the mechanism of unloading-induced elevation of Nox2 is currently unknown. Nox2 may also activate pro-fibrotic transforming growth factor β (TGF-β) as well as matrix metalloproteinase-9, thus playing a role in remodelling (Wang et al. 2010). NADPH oxidase 4 (Nox4) has recently been shown to be present in both the heart and skeletal muscle. Nox4 has been shown to regulate a pO2 -dependent Ca2+

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release by ryanodine receptor calcium channels in the sarcoplasmic reticulum (Sun et al. 2011). In addition, Nox4 can stimulate overloading-induced hypertrophy with neuronal nitric oxide synthase by activating the non-voltage-dependent Ca2+ channel trpv1 (transient receptor potential channel, subfamily V, type 1) (Ito et al. 2013). Increased levels of Nox4 were recently detected in the heart of dystrophin-deficient mice (Spurney et al. 2008), and appear to be contributory to cardiac fibrosis and pathology with Duchenne muscular dystrophy (Spurney et al. 2008). Superoxide anions and hydrogen peroxide can also function as substrates for Fenton and Haber–Weiss reactions, catalysed by transition metals (iron, copper). The Haber–Weiss reaction generates hydroxyl radicals (•OH), which are highly reactive and promiscuous, oxidizing neighbouring molecules (Halliwell, 1995). Lipid peroxidation, a chain reaction of oxidation in lipid membranes, can be initiated by hydroxyl radicals. Hydroperoxides, lipid radicals and aldehydes are generated via lipid peroxidation and can damage proteins, DNA and carbohydrates. Cellular antioxidant protection. In order to regulate ROS

levels and their participation in cell signalling, an antioxidant system of scavengers and enzymes serves to reduce potential pathological effects of high levels or exposure to ROS. Non-enzymatic, aqueous antioxidant scavengers include reduced glutathione (GSH), urate, coenzyme Q, ubiquinone and ascorbate (vitamin C) (Powers & Hamilton, 1999). Lipid soluble cellular and serum antioxidants include β-carotene, retinol and α-tocopherol (vitamin E) (Powers & Hamilton, 1999). Thus antioxidant capacities of the cytosol and lipid membrane microenvironments (e.g. plasma membrane and mitochondrial) are bolstered via scavenger molecules. An integrative system of antioxidant enzymes serves to maintain reactive species in a range that (a) promotes physiological cell signalling and (b) minimizes oxidative damage and pathology. An imbalance between sources of ROS and antioxidant enzyme and scavengers yields high oxidative stress and oxidative damage. A family of superoxide dismutases (SOD) removes O2 •– as a reactant and produces H2 O2 . A copper, zinc-dependent isoform of superoxide dismutase (Sod1 or Cu/ZnSOD) sequesters cytosolic O2 •– and yields H2 O2 . Sod2 (also termed MnSOD) is a manganese-dependent, mitochondrially localized isoform that catalyses the reduction of O2 •– to H2 O2 . An extracellular superoxide dismutase (Sod3 or EC-SOD) also exists and also uses copper and zinc as a co-factor. EC-SOD is bound to the extracellular matrix of vascular and other tissues. EC-SOD binds to heparin sulfate moieties of proteoglycan aggregates and collagen in the extracellular matrix. C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society

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Hydrogen peroxide and hydroperoxides are removed by GSH, protein thiol groups and a layered system of enzymes that include catalase, glutathione peroxidases, thioredoxins, peroxiredoxins and glutaredoxins. Reduced glutathione sequesters hydroperoxides and nitric oxide, and regulates cell signalling stimulated by reactive species. Catalase catalyses the decomposition of H2 O2 to O2 and H2 O with high flux. A single catalase molecule converts millions of molecules of hydrogen peroxide to water and oxygen per second (Goodsell, 2004). Catalase is a large tetramer with each subunit powered by a porphyrin haem group, and is usually located in peroxisomes, although peroxiredoxins also scavenge significant H2 O2 . Peroxisomes sequester H2 O2 to protect the remainder of the cell. While genetic ablation of catalase does not adversely affect development, a reflection of the redundant nature of enzymes that remove hydroperoxides, catalase deficiency has been linked to an increased risk of Type II diabetes (Goth, 2008) and appearance of grey hair (Wood et al. 2009). In contrast, a transgenic mouse that expresses a mitochondria-specific catalase has an increased lifespan, suggesting increased H2 O2 accelerates the ageing process (Schriner & Linford, 2006). A family of glutathione peroxidases remove H2 O2 and hydroperoxides; they are located in the cytosol and mitochondria and can be selenium dependent or independent. There are eight isoforms of glutathione peroxidase (GPX), GPX1–8 (Bermingham et al. 2014). The preferred substrate for selenium-dependent GPX1 is H2 O2 . GPX4 resides in a phospholipid environment and is critical to the removal of lipid peroxides. GPXs use for reducing power GSH, which is regenerated from glutathione disulfide (GSSG) by glutathione reductase. In mammalian skeletal muscle and cardiac tissue, NADPH needed for regeneration of GSH via glutathione reductase is produced by NADPH-specific isocitrate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase (Lawler et al. 1993a). Thioredoxin reductases are similar in structure to glutathione reductase and are important catalytic proteins for reducing thioredoxin; they remove hydroperoxides in the cytosol and mitochondria and participate in cell signalling. In skeletal muscle and heart, thioredoxin reductase (Trx) 1 protects cytosolic components while Trx2 guards mitochondria against damaging hydroperoxides and aldehydes. Thioredoxin contains dithiol-disulfide active sites and facilitates cysteine thiol-disulfide exchange. Overexpression of thioredoxin reduces chronic inflammation and increases lifespan (Yoshida et al. 2005). Peroxiredoxins and glutaredoxins also sequester cellular hydroperoxides that use GSH, ascorbate, or thioredoxin as reducing molecules. There are six peroxiredoxin isoforms that control cytokine-induced peroxides, mediate cell signalling, and regulate circadian rhythms. All C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society

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peroxiredoxins target H2 O2 , with peroxiredoxin-4 present specifically in mitochondria (Nonn et al. 2003). Glutaredoxins are small proteins important in supporting hydroperoxide removal by reducing oxidized ascorbate, peroxiredoxins and methionine sulfoxide reductase (Fernandes & Holmgren, 2004). Glutaredoxin’s disulfide bond is reduced via GSH oxidation, and participates in transport of iron–sulfur clusters to target proteins as needed (Rouhier et al. 2008). Glutaredoxin-2 exists in mammals as cytosolic and mitochondrial isoforms. Heat shock proteins. Heat shock proteins (HSPs) are stress-protective proteins that serve (a) as chaperones of nascent or partially oxidized proteins, (b) to reduce skeletal muscle proteolysis, (c) in recycling old proteins, (d) in nitric oxide signalling, (e) in the immune response, and (f) in repair and regeneration (Schlesinger, 1990). Heat shock proteins are responsive or inducible with a variety of stressors including heat, cold, mechanical stress, metabolic stress and exercise (Kregel, 2002). Expression of many of the HSPs is regulated by the transcription factor heat shock factor-1 (HSF-1). Most of the HSPs are named in accordance with their molecular mass in kilodaltons: HSP20, HSP27, HSP60, HSP70 and HSP90. However, αB-Crystallin and other small molecular mass HSPs are increasingly recognized in cell signalling and stress protection (Martindale & Holbrook, 2002). Many of the HSPs are up-regulated with acute and chronic bouts of exercise (Naito et al. 2001; Morton et al. 2006). HSPs protect skeletal muscle and heart against injury and loss of mass. Overexpression of HSP25 and HSP70 prevents up-regulation of FoxO3a activation, ubiquitin ligases and muscle atrophy with mechanical unloading (Senf et al. 2008). Overexpression also reduced skeletal muscle damage and disruption of Ca2+ homeostasis in an mdx mouse. In addition, overexpression of HSP70 also reduces sarcopenia, muscle damage and fibre loss incurred with the ageing process (McArdle et al. 2004; Broome et al. 2006). Interestingly, cardiac muscle is much more thermosensitive than skeletal muscle (Ali et al. 1997). It has also been shown that the inducible form of HSP70 known as HSP72 remains less responsive to exercise performed in cold conditions compared to warm conditions in the myocardium (Hamilton et al. 2001; Quindry et al. 2007). HSP70 also protects the heart against ischaemia–reperfusion injury (Starnes et al. 2003, 2005).

Inducibility of antioxidant and stress response proteins with exercise

It is well documented that ROS levels or ‘oxidative stress’ increases during a bout of acute exercise (Bejma & Ji, 1999). The spike in ROS during exercise is intensity and time dependent (Munoz Marin et al. 2010). In response to the oxidant spike during exercise, many of the antioxidant

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Superoxide dismutase and exercise. Isoforms of SOD

(Ji et al. 2007), and AMP kinase (AMPK) (Brandauer et al. 2015). Fibre-type differences in SOD inducibility with exercise are also evident. Slow twitch and Type IIa fibres have higher levels of MnSOD and Cu/ZnSOD than white muscle (Type IIb, IIx) (Powers et al. 1994; Hollander et al. 1999). MnSOD was inducible in red, but not white, skeletal muscle in response to exercise training (Pereira et al. 1994). Antioxidant enzymes in red gastrocnemius were most responsive to exercise training (Powers et al. 1994). Cu/ZnSOD did not increase in the gastrocnemius with moderate levels of exercise intensity (Song et al. 1996). Enhancement of SOD by exercise appears to be intensity dependent. Jump-training increased skeletal muscle levels of SOD and the coupled enzymes glutathione peroxidase and glutathione reductase in human subjects (Ortenblad et al. 1997). Eccentric exercise increased Cu/ZnSOD in the rectus femoris (Radak et al. 2013). High intensity exercise was needed to up-regulate SOD activity in the myocardium (Powers et al. 1993). In contrast, lifelong light-intensity exercise does not increase SOD1 (Cobley et al. 2014), although this may be confounded by interaction with ageing. For example, land and water shrews in the wild are able to up-regulate superoxide dismutase, catalase and/or glutathione peroxidase levels well above young adults (Hindle et al. 2010). However, very long-duration exercise (e.g. 2 h of exercise per day) may not yield increased SOD activity (Laughlin et al. 1990). These data suggest that higher intensity exercise may be necessary to protect against oxidative stress and damage, whether the exercise is acute, short-term, or across the lifespan.

increase in protein content and enzyme activity during exercise. Total activity for SOD increases in skeletal muscle after bouts of acute exercise (Lawler et al. 1993b; Powers & Lennon, 1999; Hollander et al. 2001) and habitual exercise training (Powers et al. 1993, 1999; Vincent et al. 2002; Nakatani et al. 2005; Higashida et al. 2011). SOD activity and GSH are elevated by exercise training (Husain & Somani, 1997). A divergent response among SOD isoforms may exist in skeletal muscle in response to exercise. MnSOD increased in skeletal muscle with swim training (Nakao et al. 2000). MnSOD RNA increased in the vastus lateralis with a single bout of exercise (Hollander et al. 2001). In contrast, Cu/ZnSOD protein levels were inducible without an increase in RNA transcripts (Hollander et al. 2001), suggesting translational or post-translational activation of a quiescent Cu/ZnSOD pool. Moderate levels of exercise training may increase MnSOD, but not Cu/ZnSOD, in skeletal muscles of young rats (Lambertucci et al. 2007). Exercise-induced boosting of MnSOD may protect skeletal muscle against hypoxia (Bo et al. 2014). MnSOD up-regulation with exercise appears to be triggered upstream by nuclear factor-kappaB (NF-κB) (Ji et al. 2006), mitogen-activated protein kinases (MAPK)

Catalase and exercise. Catalase activity appears to be less responsive to acute and habitual exercise training than MnSOD (Powers et al. 1994) in the gastrocnemius. However, catalase was up-regulated in the deep vastus lateralis, with a mix of Types IIa, IIb and I fibres (Luginbuhl et al. 1984), by exercise training, but not in the soleus (Ji et al. 1992) muscle, which is predominantly type I muscle. Alessio & Goldfarb (1988) found that catalase was up-regulated in red and white muscle following acute exercise. In contrast, exhaustive exercise reduced catalase levels (Ohishi et al. 1998). Laughlin and colleagues (Sexton et al. 1990) found that catalase only up-regulated when ischaemia–reperfusion was present. In addition, swim training had little effect on catalase (Toshinai et al. 1997). Food restriction may also impair the exercise effect on catalase and other antioxidant enzymes in the liver, while only impairing catalase in the gastrocnemius (Filaire et al. 2009). Since this study did not alter the nutritional make-up of the chow, but only restricted access to the food from ad libitum to 1 h per day, it is not known whether the impairment was due to a reduction in any specific macronutrient (Filaire et al. 2009). As expected, adenovirus transfection of a

enzymes adapt, or are inducible, with acute and repeated bouts of exercise. Li Li Ji’s and John Holloszy’s laboratories first reported in the late 1980s that skeletal muscles and the heart responded to exercise by increasing their antioxidant enzymes, including superoxide dismutase, catalase and glutathione peroxidase (Higuchi et al. 1985; Alessio & Goldfarb, 1988; Ji et al. 1988a; Ji & Fu, 1992). Heat shock proteins are also increased by exercise (Smolka et al. 2000; Fittipaldi et al. 2014); however, this may be dependent on training status and current antioxidant enzyme abundance and capacity. Subjecting a sedentary animal to exercise causes a dramatic increase in HSP72, whereas subjecting a trained animal to a bout of exercise will result in little to no change in HSP72 expression (Smolka et al. 2000). This exercise response is due in part to the antioxidant enzyme abundance and capacity of the subject prior to the exercise bout, further emphasizing the positive adaptations of exercise-induced preconditioning. In contrast, exhaustive exercise can decrease antioxidant enzyme activity, including catalase and glutathione peroxidase (Smolka et al. 2000). High levels of ROS and oxidative damage are linked to inhibition in antioxidant enzyme function with highly strenuous exercise (Davies et al. 1982; O’Neill et al. 1996). Oxidative stress during strenuous exercise was reduced by administration of a superoxide derivative (Radak et al. 1995). When muscles are able to up-regulate antioxidant enzymes in response to oxidative stress, a barrier against nucleic acid and protein oxidation is raised (Cobley et al. 2015).


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mitochondrial catalase increased exercise performance (Li et al. 2009). Regulation of catalase and integration into stress protection and mitochondrial function are emerging. Activation of the nuclear factor-erythroid-2 p45-related factor (Nrf) 2/antioxidant response element is believed to regulate exercise induced up-regulation of catalase, SOD and the glutathione peroxidase family (Li et al. 2015). Peroxisome proliferator activated receptor γ coactivator-1 (PGC-1), important in mitochondrial biogenesis, is responsive to exercise and believed to be upstream of Nrf-1 and thus catalase and other antioxidant enzymes (Kang & Li Ji, 2012). Regulation of cellular H2 O2 triggers p(66Shc) and FoxO3a, and elicits downstream signalling (Wang et al. 2015). The glutathione peroxidase system and exercise. The family of glutathione peroxidases and/or GSH is fairly consistently up-regulated in skeletal muscle and heart in response to acute and chronic exercise (Leeuwenburgh et al. 1997). Selenium-dependent and -independent GPX have been shown to be inducible with exercise. In addition, exercise has also increased glutathione peroxidase, responsible for regenerating GSH from GSSG, in some skeletal muscle studies (Ji et al. 1988b). Chandan Sen’s and Li Li Ji’s laboratories demonstrated that reduced and total glutathione levels increased in skeletal muscle in response to exercise training (Leeuwenburgh et al. 1994; Sen, 1999). Acute exercise also stimulated the liver to release glutathione as a reinforcement for blood and contracting skeletal muscle glutathione (Lew et al. 1985). Strenuous exercise bouts increased glutathione peroxidase and glutathione reductase in rat skeletal muscle (Ji & Fu, 1992). Glutathione peroxidase and glutathione reductase activities also increased in humans with intense exercise (Ortenblad et al. 1997). Glutathione peroxidase is increased with acute and long-term exercise training in young animals, but inducibility may be lost with ageing (Lawler et al. 1993b; Gunduz et al. 2004). Alessio and Goldfarb first showed that exercise-induced enhancement of antioxidant enzymes was linked to protection against exercise-induced lipid peroxidation. The glutathione peroxidase family enhancement is regulated in part by the transcription factor Nrf-2 and PGC-1 (Kang & Li Ji, 2012; Li et al. 2015). NADPH is used as a reducing equivalent by glutathione reductase to power the conversion of GSSG to GSH. In skeletal muscle, the NADP-specific isocitrate dehydrogenase, malic enzyme and the pentose phosphate shunt enzyme glucose-6-phosphate dehydrogenase produce NADPH, which can be used for the glutathione peroxidase system, nitric oxide synthases, lipid synthesis and immune response. While glucose-6-phosphate dehydrogenase is inconsistently C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society

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affected by exercise (Schulpis et al. 2008), NADP-specific isocitrate dehydrogenase is substantially responsive to exercise training (Lawler et al. 1994; Lawler & Demaree, 2001). Conversely, disuse or mechanical unloading significantly impairs NADP-specific isocitrate dehydrogenase, in concert with changes in glutathione peroxidase (Lawler et al. 2006b). Thus the glutathione peroxidase family responds in a coordinated manner to both increased and decreased use in skeletal muscle. During disuse, alterations in antioxidant and HSP levels are permissive or exacerbate oxidative stress in unloaded skeletal muscle (Lawler & Hindle, 2011). Howlett & Willis (1998) proposed that NADP-specific isocitrate dehydrogenase and mitochondrial transhydrogenase were more important in red muscle, where basal levels of ROS and hydroperoxides are higher, than in white skeletal muscle. Indeed, fibre-type differences between slow- and fast-twitch fibres between glutathione peroxidase and NADP-specific isocitrate dehydrogenase are similar. Thioredoxin, peroxiredoxin, glutaredoxin reductases and adaptation to exercise. Thioredoxins, peroxiredoxins

and glutaredoxins provide significant support to the glutathione peroxidase system in removing and regulating hydroperoxides in the cytosol, peroxisomes, cell membranes and mitochondria. Exercise stress induction of thioredoxin was first reported in plasma mononuclear cells (Sumida et al. 2004). Thioredoxin 1 up-regulation with exercise was linked to protection against the risk of Type II diabetes (Lappalainen et al. 2009). Elevation of thioredoxin and thioredoxin reductases with exercise regulated reversible oxidative, cytoprotection and thiol protein–protein interactions (Radak et al. 2013). α-Lipoic acid enhanced the exercise-induced increase in thioredoxin reductase (Kinnunen et al. 2009; Lappalainen et al. 2010). Up-regulation of mitochondrial Trx2 appears to be a critical response in the heart to exercise, by reducing mitochondrial H2 O2 flux when rats were fed a high fat + high sugar diet (Fisher-Wellman et al. 2013). Interestingly, mitochondrial Trx2 in the red gastrocnemius was only up-regulated with exercise in the absence of the high fat + high sugar diet (Fisher-Wellman et al. 2013). Glutaredoxins may respond to exercise, but evidence is limited (Lappalainen et al. 2010). Induction of peroxiredoxin-5 (PRDX5) with exercise was first reported in Type II diabetic men, with minimal response from other peroxiredoxins (Brinkmann et al. 2012). However, peroxidredoxins can over-oxidize in pathological conditions during strenuous exercise (Brinkmann & Brixius, 2013). In addition, over-oxidation of peroxiredoxins was also noted after ultra-marathon races, which persisted for a week (Turner et al. 2013). Heat shock proteins in exercise. Exercise produces thermal stress, mechanical stress, metabolic stress and

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oxidative stress, all of which can stimulate a family of inducible heat shock proteins (Fehrenbach & Niess, 1999). HSP70, HSP25, αB-crystallin and glucose-related protein 94 (grp94) levels are elevated with acute and chronic exercise training (Huey & Meador, 2008; Ogata et al. 2009). For example, HSP70 and HSP90 respond profoundly (200–1000%) to exhaustive exercise in human skeletal muscle, peaking at 3–6 days after exercise (Khassaf et al. 2001). Resistance training also stimulates an increase in HSP70 and HSP25 by over 900% in skeletal muscle (Murlasits et al. 2006). Uphill running induced higher levels of HSP70 than downhill running in slow-twitch muscles (Lollo et al. 2013). HSPs in slow-twitch and fast-twitch skeletal muscle respond to exercise training (Bombardier et al. 2013), although red muscle may experience a greater magnitude of protein abundance (Lewis et al. 2013). HSP25 and αB-crystallin may be more responsive to endurance training than resistance training, whereas HSP70 is induced by high and moderate intensity exercise (Folkesson et al. 2013). Recently, lifelong wheel running was shown to elevate HSP25, associated with protection against apoptosis and sarcopenia (Kim et al. 2015a). HSP70 and HSP25 are also up-regulated in cardiac muscle with exercise training (Lawler et al. 2006a; Lollo et al. 2013). Elevations of protein levels for HSP70 and other heat shock proteins in response to exercise occur rapidly, progressing from transcription and translation to active protein in approximately 60 min (Cumming et al. 2014). Rapid synthesis of viable heat shock protein provides swift stress protection against damage to proteins, lipids and nucleic acids. Up-regulation of HSPs during exercise provides protection against partially oxidized proteins and proteins undergoing unfolding, and protects against oxidative stress (Smolka et al. 2000). Tim Koh’s laboratory noticed that HSP25 and phosphorylated HSP25 translocated to the extracellular matrix (endomysium) when mechanical loading was altered (Koh & Escobedo, 2004). HSP25 and αB-crystallin also shift to the cytoskeleton with resistive exercise in humans, responding within 1 h and subsiding in 24–48 h (Cumming et al. 2014). Mechanical stretch, heat and contractile force are believed to activate HSPs. Many of the heat shock factors are regulated by the transcription factor HSF-1. Exercise training also up-regulated HSF-1, as an upstream mechanism behind exercise-induced increases in HSPs (Atalay et al. 2004). HSF-1 protein levels and activity are increased in the heart with exercise training (Demirel et al. 2003). HSF-1 induction can occur with a loss of reduced glutathione, signifying that increased expression of HSP is triggered by insufficient antioxidant protection (Paroo et al. 2002b). Oestrogen can up-regulate HSP70 in the heart via NF-κB activation of HSF-1 (Hamilton et al. 2004). However, oestrogen may also blunt exercise-induced up-regulation of HSP70 (Paroo

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et al. 2002a; Bombardier et al. 2013). Sex differences have been observed in the expression levels of HSPs. In cardiac muscle, females express higher endogenous levels of HSP72, but evidence suggests that males and ovariectomized rats may be more sensitive to stressors, such as exercise, enabling them to better enhance their expression of HSPs (Paroo et al. 2002a; Bupha-Intr & Wattanapermpool, 2004). Conversely, disuse or mechanical unloading (bedrest, casting, spaceflight) causes a down-regulation of HSP70, HSP25 and HSF-1 (Lawler et al. 2006b; Senf et al. 2008; Lawler & Hindle, 2011). Thus HSPs are highly sensitive to both increased and decreased mechanical unloading. With increased oxidative stress during unloading (Lawler et al. 2003), rapid proteolysis is essential to remove partially oxidized proteins, particularly because of loss of protective HSPs. Overexpression of HSP70 and HSP25 protect against FoxO3a activation and proteolysis (Senf et al. 2008). Reducing oxidative stress during disuse also protects against FoxO3a activation and muscle fibre atrophy (Lawler et al. 2014). Up-regulation of HSPs including HSP70 indeed has been postulated to reduce oxidative stress, particularly during high intensity exercise when antioxidant status is impaired (Smolka et al. 2000). Thus heat shock proteins can be conceived as a second line of defence against oxidative damage. Hormesis – stress response to exercise. Allan Goldfarb,

John Holloszy and Li Li Ji were among the first investigators to characterize adaptation of antioxidant enzymes to mild to moderate oxidative stress that occurs during exercise (Higuchi et al. 1985; Ji, 2002; Bloomer et al. 2005). Training reduced oxidative stress in response to an acute bout of exercise (Alessio & Goldfarb, 1988; Ji et al. 1988a, 1992; Bloomer et al. 2005). Adaptations of antioxidant enzymes to exercise in skeletal muscle and heart were dependent upon exercise intensity, duration and age (Hammeren et al. 1992; Powers et al. 1993). Hormesis is commonly defined as a beneficial effect conferred by a low dose of an agent or phenomenon that would cause injury or toxicity at high levels. Li Li Ji’s laboratory first used the term hormesis to describe this adaptation in 2006 (Ji et al. 2006). The pro-inflammatory transcription factor NF-κB and MAPK were identified as part of a signalling cascade stimulated by exercise which up-regulated MnSOD and inducible nitric oxide synthase (Ji et al. 2006). Exercise-induced signalling was initiated by xanthine oxidase, as use of allopurinol blunted exercise-induced activation of NF-κB and MnSOD. ROS activate NF-κB by phosphorylating serine residues on the inhibitor of κB (I-κB), an inhibitor usually bound to quiescent NF-κB. Phosphorylation of I-κB releases NF-κB, which then translocates to the nucleus. Hormesis was also found to be beneficial in ageing skeletal muscle as well C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society

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(Ji et al. 2010). Thus exercise-induced enhancement of antioxidant enzymes and heat shock proteins fortify a line of defence against oxidative stress and damage. In addition, hormesis allows ROS to function at physiological levels where they regulate important cell signalling related to stress protection, protein turnover, metabolism, glucose uptake, modulation of the immune system, regulation of blood flow, hypertrophy and atrophy. Furthermore, hormesis could be viewed as a process that explains the exercise preconditioning effect articulated by Zsolt Radak (Radak et al. 2000). Mild oxidative stress induced by exercise stimulates increased protection against oxidative stress, metabolic stress, mechanical stress, hypoxia, ischaemia, heat, cold and other perturbations of homeostasis. More recently, the notion of mitochondrial hormesis and exercise has been proposed (Ristow & Zarse, 2010). Up-regulation of mitochondrial antioxidant enzymes, sirtuins and PGC-1 with exercise is thought to provide protection against Type II diabetes and ageing (Balestrieri et al. 2015). Mitohormesis via NADPH producing pathways (e.g. NADP-specific isocitrate dehydrogenase) and glutathione homeostasis may stimulate a biosynthetic serine–1-carbon–glycine pathway and the longevity-promoting polyamine spermidine (Ost et al. 2015). Because pro-oxidant and pro-inflammatory mediators are highly integrated into normal skeletal muscle and cardiac function, including remodelling and resisting thermal, metabolic, hypoxic and mechanical stressors, exercise hormesis is becoming an active focus of research (Peake et al. 2015). Recently, NADPH oxidases were identified as requisite for exercise preconditioning in the heart (Frasier et al. 2013). Identification of transcription factors, antioxidant enzymes, ROS sources, heat shock proteins, kinases, mechanotransduction and other signalling pathways involved will be crucial to our understanding of striated muscle adaptations (Alleman et al. 2014; Peake et al. 2015). What doesn’t kill you, indeed makes you stronger. The following portion of this review will focus on translational benefits of hormesis or exercise preconditioning and clinical benefits. Exercise preconditioning and ischaemia–reperfusion.

The notion of exercise preconditioning is that transient, mild to moderate oxidative stress during exercise stimulates the up-regulation of protective antioxidant and stress proteins. Enhancing antioxidant and other stress proteins fortify cellular resistance to oxidative damage, injury, inflammation and chronic disease. Ischaemia, and in particular ischaemia followed by profound perfusion, results in tissue damage (Farb et al. 1993). Tissue damage can actually be far greater during the reperfusion phase than during ischaemia itself, due to high levels of oxidative stress and Ca2+ influx (Starkov et al. 2004). Indeed, the surprisingly large damage that occurs C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society

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during reperfusion has been termed ‘the oxygen paradox’ and ‘the calcium paradox’ (Hearse et al. 1978). However, ischaemia may prime reperfusion with dire consequences (ischaemia–reperfusion; I/R), as a dramatic reduction in levels of superoxide dismutase and catalase has been reported after I/R (Laughlin et al. 1990). In addition, I/R suppresses sirtuin (SIRT) 1, a protective histone deacetylase linked to longevity involved in elevation of AMPK phosphorylation and PGC-1 (Cattelan et al. 2015). During ischaemia, mitochondria are starved of oxygen, and cardiac cells shift metabolism to glycolysis (Buja, 2005). Hydrogen ions and lactate levels increase, decreasing pH below 6.5. Na+ /H+ exchange and Na+ /K+ pumps are compromised as ATP levels are challenged (Borges & Lessa, 2015). Reperfusion causes a burst of ROS and greatly exacerbates Ca2+ influx and damage. Sarcoplasmic reticulum Ca2+ pumps (sarco/endoplasmic reticulum calcium ATPase, SERCA) are impaired by oxidative stress and lower ATP, thus contributing to calcium overload (Grover & Samson, 1988; Grover et al. 1992; Ermak & Davies, 2002). As oxidized SERCA re-sequesters less Ca2+ , calcium levels rise and lead to damage and proteolysis (Murachi et al. 1981; Takahashi, 1990). There is a compensatory increase in Na+ /Ca2+ exchange as an adaptation for high internal Na+ caused when Na+ /K+ pumping is impaired during ischaemia, and the Na+ /K+ exchanger is increased during reperfusion (Hoffman et al. 2004). ROS and high cytosolic [Ca2+ ] then trigger mitochondrial permeability transition pore opening and myofibrillar hypercontractility as pH rises (Razvickas et al. 2013). In addition, cardiac ischaemia also down-regulates HSP70, SOD, catalase and glutathione peroxidase in skeletal muscle (Lawler et al. 2006a), thus reducing cardioprotection. Reduction of MnSOD in heart expose to I/R has been cited as contributory to damage (French et al. 2008). Influence of exercise preconditioning in striated muscle

As discussed in the previous section, skeletal and cardiac muscles are highly responsive to single and regular bouts of exercise. Increased activity due to stressors such as exercise can precondition the striated muscle tissues, thus building up defence mechanisms. This section will provide an overview of the cellular adaptations that lead to exercise preconditioning. Antioxidant enzymes and exercise preconditioning.

Exercise that is performed prior to ischaemia and reperfusion provides defence for the myocardium and skeletal muscle against I/R injury, a phenomenon often termed exercise preconditioning (Radak et al. 2000). Exercise-induced cardioprotection and skeletal muscle

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resistance against ischaemia–reperfusion injury appear to be conferred by (a) up-regulation of antioxidant capacity, (b) elevation of critical heat shock proteins, (c) increase in nitric oxide signalling, (d) up-regulation of KATP channels, and (e) increased δ-opioid receptors. In skeletal muscle MnSOD, catalase and glutathione peroxidase are up-regulated with exercise training and are linked to prevention of I/R injury (Pereira et al. 1994; Quindry et al. 2005). In the heart MnSOD and catalase are consistently inducible with exercise training and have been linked to cardioprotection (Hamilton et al. 2001; Harris & Starnes, 2001; Lennon et al. 2004b; Moran et al. 2005; French et al. 2008; Kavazis et al. 2008; Quindry et al. 2010, 2012; Esposito et al. 2011). Exercise training increased antioxidant enzymes in concert with improvement of mitochondrial function during I/R (Kavazis et al. 2008). Powers and colleagues demonstrated that exercise-induced up-regulation of MnSOD is causal in cardioprotection against I/R injury by using antisense oligonucleotides to knockdown MnSOD (French et al. 2008; McClung et al. 2010). Indeed, knockdown of the MnSOD gene removed most of the cardioprotection against infarct size, impairment of cardiac function and oxidative damage. Interestingly, the exercise cardioprotective effects appear to be acute rather than chronic, meaning that habitual exercise is needed to retain the beneficial effects of exercise preconditioning. Each bout of exercise confers a cardioprotective benefit that lasts approximately 72 h (Yamashita et al. 1999; Lennon et al. 2004a). Heat shock proteins and exercise preconditioning. Many of the members of the heat shock protein family are inducible with exercise training, and have been linked to cardioprotection: αB-crystallin, HSP10, HSP60, HSP70 and HSP90. Higher intensity exercise appears to induce a greater increase in HSP70 than moderate intensity exercise (Lennon et al. 2004b). Starnes et al. (2005) also found that moderate intensity exercise (50–60% V˙ O2 max ) resulted in a small up-regulation of HSP70. Long-term exercise training (24 weeks) increased HSP70 protein expression, without an increase in MnSOD and glutathione reductase (Moran et al. 2005). Antioxidant supplementation appears to lead to a reduction in myocardial HSP72, but this reduction does not attenuate the enhanced MnSOD activity or the overall exercise-induced protection of the myocardium (Hamilton et al. 2003). Harris & Starnes (2001) modulated body temperature to tease out the most important heat shock proteins in exercise preconditioning. Exercise, while allowing body temperature rise, increased HSP70 protein abundance in the heart and skeletal muscle. In the wetted, cold exercise groups, αB-crystallin and HSP90 were significantly elevated, but HSP70 remained unchanged. Suppressed inducibility of HSP70 to exercise when

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internal temperature was thermally neutral was linked to a dramatic attenuation of protection of cardiac function during ischaemia–reperfusion. Hamilton et al. (2001) and Quindry et al. (2007) found that HSP70 was elevated by exercise training at 70% max for 3–5 days/week under warm, but not cold, conditions. In contrast, glutathione peroxidase was up-regulated during exercise in the cold, and linked to cardioprotection (Hamilton et al. 2001). Protection against apoptosis after I/R was retained by cold exposure during exercise (Quindry et al. 2007) suggesting a independent mechanism for regulating apoptosis. Consistent with the above observations, heat stress up-regulates HSP70 and enhances myocardial recovery after ischaemia–reperfusion injury (Currie et al. 1988). HSP70 can be localized in the cytosol and mitochondria, but it is not clear whether mitochondrial HSP70 is more cardioprotective against I/R. However, Williamson et al. (2008) found that overexpression of a mitochondria-specific HSP70 provided protection against mitochondria and electron-transport chain damage. In short, HSP70 induction by exercise training appears to be most effective when body temperature rises, when exercise intensity or duration are high, when effects are on mitochondria, and when supplemented with antioxidants. KATP channels and exercise preconditioning. ATPsensitive K+ (KATP ) channels in cardiomyocyte and vascular smooth muscle cells (VSMCs) have recently been found to be protective against damage and infarct size in the heart. Exercise training has been found to enhance re-oxygenation of mitochondria. Exercise training increased protein expression of Kir6.1, a subunit of VSMC sarcolemmal KATP (sarcKATP ) channels (Li et al. 2014). Increased KATP channels in VSMCs was linked to better blood flow and oxygenation. Inhibition of KATP channels via gene transfer of the dominant negative Kir6.1AAA delayed recovery and enlarged the size of the infarct (Li et al. 2014). Quindry et al. (2010) used specific inhibitors of mitochondrial KATP (mitoKATP ) and sarcKATP channels to demonstrate a causal relationship of exercise-related cardioprotection against ischaemia–reperfusion injury. Inhibition of mitoKATP channels abrogated the exercise training effect. In addition, up-regulation of mitoKATP channels during exercise was linked to a reduction of cardiac arrhythmias during I/R (Quindry et al. 2012). An emerging role for the KATP channel is its ability to regulate and reduce oxidative stress. Diazoxide, a mitoKATP channel agonist, reduces oxidative stress by protecting protein thiols and increasing levels of reduced glutathione, abrogated by KATP channel blockers (Lemos Caldas et al. 2015). Indeed, diazoxide has a significant preconditioning effect on the heart, up-regulating pro-survival genes (e.g. VEGF, Bcl-2, PCNA, SDF-1a) and Akt phosphorylation (Mehmood et al. 2015). Progenitor cell survival is C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society

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enhanced via mitoKATP channel activators (Mehmood et al. 2015). Conversely, hyperlipidaemia can attenuate mitoKATP channels and thus impair oxidative stress and increase oxidative stress in the heart (Csonka et al. 2014). Because H2 O2 can act on KATP channels (Melo et al. 2015), it can be argued that ROS initiate a preconditioning effect on cardioprotection in part through KATP channels. Thus enhancement of mitochondrial oxygen flux and KATP channels may be central to managing oxidative stress and exercise preconditioning in the heart. δ-Opioid receptors and exercise preconditioning. Opioid peptide receptors are part of the G-protein coupled receptor family. Recent and exciting literature has also provided evidence that opioid receptors may be another limb of exercise preconditioning. δ-Opioid receptors have been shown to reduce mitochondrial electron chain damage and induce neuroprotection (Zhu et al. 2009). In addition, δ-opioid receptors reduced oxidative stress through a protein kinase C (PKC) pathway in glial cells (Zhou et al. 2013). δ-Opioid receptor agonists reduce mitochondrial permeability transition pore opening and morphological changes in mitochondria (Zeng et al. 2011). P38/MAPK signalling has been implicated in δ-opioid receptor cardioprotection (Peart et al. 2007). Epicatechins, found in high concentrations in a variety of flavanol-rich foods and beverages such as green tea, dark chocolate, cocoa, black grapes, cherries and apples, are potent antioxidant and anti-inflammatory nutraceuticals. Recently, epicatechin was shown to have δ-opioid receptor binding activity and to improve mitochondrial state 3 respiration, thus stimulating preconditioning (Panneerselvam et al. 2013). Exercise training up-regulates δ-opioid receptors in the heart, and that effect contributes to cardioprotection. Michelsen et al. (2012) showed that blockade of δ-opioid receptors dampened exercise preconditioning of the heart. Furthermore, δ-Opioid receptor blockade limits exercise preconditioning in reducing infarct size (Dickson et al. 2008; Galvao et al. 2011). Exercise attenuation of necrosis, but not apoptosis, was linked to δ-opioid receptor signalling (Miller et al. 2015). Mitophagy and exercise preconditioning. Regular bouts

of physical activity result in an expansion of the mitochondrial pool in skeletal muscle in an effort to meet the metabolic demands and improve endurance performance (i.e. reduce fatigability). Exercise-induced remodelling and turnover of the mitochondrial pool improves the overall quality of the mitochondria through turnover via degradation and biogenesis. Maintaining quality of the mitochondrial pool requires the elimination of damaged and/or dysfunctional mitochondrial fragments. Impaired portions of the


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reticulum are isolated from the healthy portions via fission, and are then tagged for selective degradation by macro-autophagy. Organelle recycling via degradation of damaged mitochondrial fragments by macro-autophagy is a process often referred to as ‘mitophagy’. Mitophagy is thus a quality control system that optimizes highly functioning mitochondria. Autophagy is regulated by several autophagy-related genes (e.g. atrogins), including Atg6, which is better known as Beclin. Tagging of the fissioned mitochondrial fragments for degradation occurs through mitophagy-specific receptors, such as Bcl2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) (Lee et al. 2011; Rikka et al. 2011), or by ubiquitination of outer membrane proteins of the mitochondria by E3 ligases such as Parkin (Narendra et al. 2008; Geisler et al. 2010). Tagged mitochondria are eventually engulfed by the autophagosome before being degraded by the lysosome. Autophagy flux is often estimated by the ratio of microtubule associated protein light chain 3 (LC3) II to LC3-I, where a shift in the LC3-II:LC3-I ratio indicates increased flux, and lower levels of p62/sequestosome 1, which is degraded when it escorts tagged cellular fragments to the autophagosome (Mizushima et al. 2008). In skeletal muscle, voluntary wheel running has been shown to elevate levels of Beclin protein, reflective of an improved ability to induce autophagy (Lira et al. 2013; Greene et al. 2015). Aerobic exercise increases levels of mitochondrially localized LC3-II, p62 and ubiquitination (Saleem et al. 2014). In addition, Vainshtein et al. (2015) found that a single bout of exercise is capable of enhancing mitochondrial localized LC3-II, Parkin and elevated ubiquitination of the mitochondrial fraction. PGC-1 has been cited as an important upstream regulator of mitochondrial quality (Greene et al. 2015). From these findings it appears that mitophagy-related signalling and flux are enhanced after just a single bout of exercise. Of primary interest is whether a regular exercise regimen can elicit resting state adaptations in skeletal muscle tissue. Lira et al. (2013) determined that 4–5 weeks of voluntary wheel running was capable of enhancing basal autophagy and mitophagy protein expression. Overall, the limited data available suggest that regular exercise has an additive effect in skeletal muscle that eventually leads to improved autophagy and mitophagy capacity during exercise itself, as well as improved clearance at rest. The role of autophagy in cardiac muscle is often assumed to protect the myocardium against the accumulation of aggregates and dysfunctional mitochondria that can emit cell death (apoptosis) signals. In contrast, findings from skeletal muscle suggest that autophagy and mitophagy also contribute to regulation of energy homeostasis and metabolic stress in response to exercise (He et al. 2012a; Jamart et al. 2013; Lira et al. 2013;

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Greene et al. 2015). Studies have shown that in response to acute (Ogura et al. 2011; He et al. 2012b) and chronic (Willis et al. 2013) exercise, autophagy is increased in cardiomyocytes. While data examining the influence of exercise-induced mitophagy in the myocardium are scarce, evidence from ischaemic preconditioning (IPC) can offer indications of what might occur. Following a period of cardiac ischaemia, ridding the cardiomyocytes of damaged and/or dysfunctional mitochondria is thought to protect the cells. IPC leads to mitochondrially localized Parkin, tagging the mitochondria for mitophagic degradation (Huang et al. 2011; Kubli et al. 2013), whereas Parkin-deficient mice accumulated dysfunctional and/or damaged mitochondria (Huang et al. 2011; Kubli et al. 2013). Parkin knockout mice exhibited decreased p62 protein, localized to the mitochondria in response to infarction (Huang et al. 2011). In response to ischaemic injury, elevated levels of tumour suppressor p53 are capable of reducing mitophagy by functioning as a negative regulator of BNIP3 and ROS signalling (Hoshino et al. 2012). Together, these findings suggest that the remodelling that occurs post-infarction involves clearance of damaged and/or dysfunctional mitochondria in an effort to protect against apoptosis and cardiomyocyte loss. Evidence presented here indicates it is likely that the stress of regular exercise can precondition the myocardium similarly to what has been seen in IPC and exercise models. The potential role(s) of ROS during exercise-induced mitophagy remain unclear. Exercise is known to increase the expression of regulators of mitochondrial remodelling (Ding et al. 2010; Perry et al. 2010; He et al. 2012b; Lira et al. 2013), possibly through contraction-induced ROS release (Fan et al. 2010). Recent findings suggest that ROS signalling is crucial for the promotion of mitophagy following ischaemia (Hoshino et al. 2012) and the enhancement of autophagy following exercise (Lo Verso et al. 2014). Lo Verso et al. (2014) found that chronic antioxidant treatment inhibits autophagy, and is therefore detrimental to the exercise-induced adaptations. Prolonged use of N-acetyl cysteine, as well as short-term use of the mitochondria-targeted antioxidant Mito-TEMPO, led to impaired performance and mitochondrial function in exercised mice (Lo Verso et al. 2014). These results highlight the importance of mild levels of oxidative stress, including that of mitochondria-derived ROS, produced during exercise, which lead to improved quality of the mitochondrial pool via mitophagy-driven remodelling. Future studies should examine the impact and mechanisms of exercise-induced ROS signalling in the mitochondrial remodelling process, including mitophagy. Other avenues of interest include the intensity and/or duration of exercise needed to elicit remodelling and mitophagy flux, as well as the identification of the various potential sources of ROS.

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Exercise preconditioning and clinical benefits in striated muscle

The many benefits derived from exercise preconditioning can significantly impact chronic disorders that negatively affect striated muscle. Throughout this section we will highlight two conditions known to lead to muscle dysfunction – ageing and Type II diabetes. Ageing, skeletal muscle wasting, and exercise preconditioning. The ability of novel exercise training to

up-regulate stress proteins including antioxidant enzymes may be compromised as age progresses. Cu/ZnSOD, GPX and catalase become unresponsive to exercise stimulus in old rats, compared with young, and MnSOD levels were significantly reduced by exercise (Lambertucci et al. 2007). Stress intolerance increases with ageing, impairing mitochondrial function, caveolae number, MAPK signalling and PKC (Peart et al. 2014). Ageing also suppressed δ-opioid receptor cardioprotection through failure of MAPK signalling (Peart et al. 2007). Thus the risk of injury from ischaemia–reperfusion is raised, while exercise protection diminishes. Indeed, infarct area increases when stressed by I/R in the ageing heart (McCully et al. 2006). Glutathione peroxides, glutathione reductase and superoxide dismutase increase in skeletal muscle with ageing, yet become unresponsive to exercise training (Leeuwenburgh et al. 1994). Navarro-Arevalo et al. (1999) found that antioxidant enzymes responded to exhaustive exercise in the heart, but not skeletal muscle. However, exercise was able to up-regulate SIRT-1 in the ageing heart, which could protect mitochondrial function (Ferrara et al. 2008). Ageing also attenuates the ability of ROS to increase and modulate low-frequency contractility in skeletal muscle (Lawler et al. 1997). Mice overexpressing MnSOD do not live longer but have reduced age-associated disease or pathology. Exercise training does increase superoxide dismutase in skeletal muscle in senescent rats, with a marked increase in cardiac MnSOD (Starnes et al. 2003; Parise et al. 2005; Lawler et al. 2009). Overexpression of MnSOD was recently found to reduce apoptosis and fibrosis in the ageing heart, acting as an exercise mimetic (Kwak et al. 2015). One year of swimming also increased SOD in the heart (Gunduz et al. 2004). Starnes et al. (2003) showed that exercise does improve post-ischaemic function, possibly related to a reduction in mitochondrial ROS production (Starnes et al. 2007). Protection of mitochondria may be the key to preserving cardioprotection and exercise preconditioning. A new study suggested that protection of mitochondrial function during I/R by exercise preconditioning in the ageing heart may be conferred by redox-sensitive ornithine decarboxylase/polyamine signalling (Smirnova et al. 2012; Wang et al. 2014). C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society

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Knockout of cytosolic Cu/ZnSOD results in a premature ageing or dystrophic-like phenotype (Muller et al. 2007). However, some of the myopathy with the global knockout is due to pathology at the neuromuscular junction (Shi et al. 2014). Conversely, overexpression of Cu/ZnSOD yields an amyotrophic lateral sclerosis-like phenotype (Shi et al. 2014). A large up-regulation of Cu/ZnSOD, without a compensatory increase in catalase or glutathione peroxidase, has also been observed during unloading-induced oxidative stress and atrophy (Lawler et al. 2006b). However, glutathione peroxidase and reduced glutathione are less inducible with exercise in skeletal muscles from old rats (Leeuwenburgh et al. 1994). Indeed, Radak et al. (2005) proposed that exercise hormesis in ageing muscle is linked to a reduced response to ROS produced during exercise. Heat shock response is also impaired with ageing. There was a 47% reduction in HSF-1 activation in the heart when Fischer 344 rats were exposed to heat stress at 41°C (Locke & Tanguay, 1996). Inducibility of HSP70 was also suppressed in old hearts when subjected to heat stress (Locke & Tanguay, 1996). High intensity, resistance exercise training also increased HSP25 and HSP70 in skeletal muscle of old rats (Murlasits et al. 2006). Concomitant with a reduced heat stress response, protection against I/R-induced damage was also lost. Reduction in HSP25 has also been linked to impaired δ-opioid signalling and cardioprotection against I/R injury (Locke & Tanguay, 1996). Lifelong exercise protects HSP25 in skeletal muscle (Kim et al. 2015a). Ageing, however, suppressed inducibility of HSP70 to heat stress and exercise in the ageing heart in a study conducted by Scott Powers’s laboratory (Demirel et al. 2003), but daily exercise increased HSP70 and HSP25 in the ageing heart in another study (Rinaldi et al. 2006). Induction of HSP in ageing skeletal muscle was dependent upon duration and frequency of exercise (Kim et al. 2015b). For example, exercise 5 days a weeks was superior in up-regulating HSP25, HSP60, HSP70, HSP90, MnSOD, Cu/ZnSOD and EC-SOD vs. 3 days a week, possibly linked to increased MAPK (Kim et al. 2015b). Heat shock proteins were inducible in slow and fast muscle with the exception of HSP27, which was responsive to exercise in slow-twitch muscle exclusively. Given that the risk of ischaemia–reperfusion injury increases with ageing, clearly far more research is needed to further our understanding of compromised mechanisms of exercise preconditioning in ageing heart and skeletal muscle. It has been suggested that exercise when combined with caloric restriction my enhance exercise preconditioning (Abete et al. 2010). In addition, the tandem of caloric restriction and exercise protected against ischaemia–reperfusion injury (Abete et al. 2005).


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Type II diabetes and exercise preconditioning. Exercise consistently improves glucose tolerance and reduces the risk of Type II diabetes (Tuomilehto et al. 2001; Mendham et al. 2015). Skeletal muscle and liver show improvement of lipid handling (Cortright et al. 2006; Jordy et al. 2015). Reduction in pro-inflammatory, pro-oxidant signalling is believed to be the primary mechanism (Barakat et al. 1983; Pilegaard et al. 2000; Cortright et al. 2006; Bikman et al. 2010b). Exercise training reduces the incidence of insulin resistance, and is linked to (a) reduced oxidative stress, (b) elevation of stress proteins (antioxidant, heat shock proteins), and (c) elevation of SIRT-1/PGC1 pathways and AMPK phosphorylation (Hawley & Lessard, 2008; Lambert et al. 2008). Indeed, prior exercise improves insulin signalling (Wojtaszewski et al. 2003) and may be protective against periodic or intermittent meals of calorically dense food. Thus the positive benefits of exercise on insulin signalling go beyond weight loss (Lambert et al. 2008). Impaired ability to handle fatty acids by mitochondria appears to be critical in elevating oxidative stress and contributing to insulin resistance (Kim et al. 2000; Boyle et al. 2012). Toll-like receptor 4 (TLR-4) has been shown to mediate oxidative stress and metabolic changes with high fat diet that leads to poor fatty acid oxidation and insulin resistance (McMillan et al. 2015). Zanchi et al. (2010) showed that resistive training suppresses TLR-4 and cytokine tumour necrosis factor-α (TNF-α) in skeletal muscle. Exercise down-regulates TLR-4 and is associated with increases in HSP70 in skeletal muscle (Rodriguez-Miguelez et al. 2014). Indeed, up-regulation of HSP70 is causal in reduction of TLR-4 in glial cells (Sinha et al. 2015). Exercise may delay or attenuate pro-inflammatory signalling by raising levels of heat shock proteins (Hooper & Hooper, 2009). Exercise also increases SIRT-1 and SIRT-3 in the heart and reduces apoptosis (Sack, 2011; Lai et al. 2014), similar to exercise preconditioning against I/R injury, the effects of exercise on glucose tolerance and GLUT4 availability are acute. Obesity and type II diabetes blunt exercise preconditioning, associated with poor inducibility of antioxidant enzymes, heat shock proteins and SIRT/PGC-1 signalling (Cappel et al. 2015). Cholesteryl ester transfer protein (CETP) shuttles lipids between serum lipoproteins and tissues, which may be a mechanism of impairment of PGC-1α and exercise response with obesity and Type II diabetes (Cappel et al. 2015). Cholesteryl ester transfer protein is reduced with exercise (Seip et al. 1993; Wilund et al. 2002) and polymorphisms have been linked to differences in high density lipoprotein cholesterol levels (Spielmann et al. 2007; Zhang et al. 2013). Large release of H2 O2 from mitochondria and mitochondrial defects are relieved by aerobic exercise

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training (Konopka et al. 2015). Nox2 inhibition by sesamin was recently found to protect against impaired mitochondrial function and reduced exercise capacity with a high fat diet (Takada et al. 2015). Thus Nox2 and mitochondrial ROS may act together as an amplifier to chronically elevate oxidative stress and impair skeletal muscle function with insulin resistance. In a highly novel study, Strobel et al. (2014) demonstrated that depletion of glutathione levels with diethyl maleate amplified the ability of exercise training to increase PGC-1α. Increased oxidative stress with exercise and diethyl maleate plus exercise was confirmed using F2-isoprostanes as a marker. Exercise training improves artery relaxation and superoxide dismutase levels in rats fed a high fat diet (de Moraes et al. 2008). These data are consistent with the hypothesis that exercise preconditioning increases mitochondrial biogenesis and protection via transient oxidative stress during each bout of exercise. Summary and conclusions

Evolution and adaptations to an atmosphere that became rich in molecular oxygen led to the development of antioxidant and stress response proteins and pathways, which confer cellular protection against a host of stressors and insults. High energy reactive oxygen and nitrogen species are indeed utilized for cell signalling and communication. Transient increases in oxidative stress and inflammatory signalling that occur during exercise are important stimuli to produce cellular adaptations that protect against higher levels of oxidative stress. This is a process known as hormesis or exercise preconditioning. Cell-protective antioxidant enzymes (e.g. MnSOD and glutathione peroxidase), heat shock proteins and SIRT/PGC-1 pathways are frequently up-regulated by exercise in the heart and skeletal muscle in response to acute or chronic bouts of exercise. A central player to exercise preconditioning appears to be the organelle captured over a billion years ago by single celled organisms to handle and harness the power of oxygen: mitochondria. In this model, protection against oxidative stress, ischaemia–reperfusion, insulin resistance and ageing depends upon adaptation of mitochondrial morphology, function and stress-protective proteins with mitochondrial location or impact (MnSOD, Trx2, HSP70, SIRT-1, PGC-1α). Recent evidence suggests that Na+ /K+ -ATPase channels and δ-opioid receptors are involved in mitochondrial adaptations to oxidative stress and exercise preconditioning. Exercise preconditioning is blunted with obesity, Type II diabetes and ageing, but also serves as a powerful and preventative therapeutic agent against those conditions. Emerging research is identifying novel molecular mechanisms that could restore and enhance exercise preconditioning during chronic disease.

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Additional information Competing interests None declared. Funding Support has been provided by grants to J.M.L. from the National Aeronautics and Space Administration (NASA; NNX13AE45G), National Institutes of Health (NIH; AR054084), National Science Foundation (NSF; 055185F), American Heart Association (AHA; 0855158F), and the Huffines Institute at Texas A&M University. J.M.H. is funded through the Strategic Research Award from the College of Education and Human Development (CEHD). Acknowledgements We wish to thank members of the Redox Biology and Cell Signaling Laboratory for thoughtful and constructive discussions concerning the manuscript.

Quantification of neurovascular protection following repetitive hypoxic preconditioning and transient middle cerebral artery occlusion in mice.

Tendon shortening in striated muscle.

Immunocytochemical localization of proteins in striated muscle.

Mitochondria, muscle health, and exercise with advancing age.

MG53 and disordered metabolism in striated muscle.

Longitudinal pulse propagation characteristics in striated muscle.

Adenine nucleotide degradation in striated muscle.

Charge movement in the membrane of striated muscle.

Striated muscle hamartoma in a newborn.

The transformational potential of striated muscle in hydromedusae.

A reexamination of the thermoelastic effect in active striated muscle.

Protection against muscle damage induced by electrical stimulation: efficiency of a preconditioning programme.

The formation of synapses in amphibian striated muscle during development.

Poorly understood aspects of striated muscle contraction.

Ischemic preconditioning accelerates muscle deoxygenation dynamics and enhances exercise endurance during the work-to-work test.

Transplantation and regeneration of striated muscle.

Structure of the cross-striated adductor muscle of the scallop.

Titin: major myofibrillar components of striated muscle.

Sensory preconditioning versus protection from habituation.

NO2- Mediates the Heart Protection of Remote Ischemic Preconditioning.

Striated muscle function, regeneration, and repair.

Effect of a prior bout of preconditioning exercise on muscle damage from downhill walking.

Renal protection: preconditioning for the prevention of contrast-induced nephropathy.

Effect of heat preconditioning by microwave hyperthermia on human skeletal muscle after eccentric exercise.