Brain has an extraordinary high metabolic rate consuming approximately 20 % of all inhaled oxygen at rest; however, it only accounts for 2 % of body weight (Silver and Erecinski 1998) . This enormous metabolic demand is due to the fact that neurons are highly differentiated cells and need large amounts of ATP in order to maintain ionic gradients across cell membranes and for neurotransmission. Since most neuronal ATP is generated by oxidative metabolism, neurons depend critically on mitochondrial function and on oxygen supply (Kann and Liang 2007).

The mitochondria have critical functions which influence neuronal excitability, including the production of adenosine triphosphate (ATP), fatty acid oxidation, excitotoxicity , apoptosis and necrosis control, amino acid cycle regulation, biosynthesis of neurotransmitters, and regulating the homeostasis of cytosolic calcium. Mitochondria are the main site of ROS production therefore they are extremely vulnerable to oxidative damage (Waldbaum et al. 2010) .

It is known that a common feature of neurotraumatic, neurodegenerative, and neuropsychiatric diseases is the presence of oxidative and nitrosative stress. Oxidative and nitrosative stress (overproduction of superoxide anions, hydroxyl radicals, hydrogen peroxide, and peroxynitrite), which may be responsible for neuronal cell dysfunction and death in above mentioned neurological disorders (Barham et al. 2004; Maes et al. 2011; Farooqui 2010). At the molecular level, these reactive species are not only detrimental to neural cells through their oxidative effects, but also through the regulation of cellular redox, which plays an important role in the modulation of critical cellular functions (mainly in astrocytes and microglia), such as mitogene-activated protein (MAP) kinase cascade activation, ion transport, calcium mobilization, and apoptosis program activation (Emerit et al. 2004; Farooqui and Horrocks 2007; Farooqui 2010). Oxidative and nitrosative stress generating pathways are interconnected and closely associated with neuroinflammatory pathways and responses, along with subsequent involvement of mitochondrial metabolic processes, which generate more highly reactive free radical species. Indeed, ROS and reactive nitrogen species (RNS) consist of active moieties that can react with neural cell lipids, proteins, and nucleic acids. Under physiological conditions defense pathways counterbalance ROS and RNS production, thus in these conditions reactive species have physiological roles that include signaling neural cell proliferation, differentiation, and growth. Under pathological conditions excessive production of ROS or RNS may result in reactions of reactive species with fatty acids, proteins, and DNA, thereby causing damage to these cellular components (Barham et al. 2004; Maes et al. 2011) . Thus, the overproduction of ROS and RNS can damage all components of the cell, leading to a progressive decline in physiological function. As stated in Chaps. 7, 8, and 9, ROS can attack proteins causing their carbonylation, which is an irreversible oxidative damage, often leading to a loss of protein function and protein aggregation (Dalle-Donne et al. 2006). Generation of peroxynitrite results in the nitration of tyrosine residues in proteins (protein nitration), leading to alterations in protein activity (Ischiropoulos 2009). Free radicals can “steal” electrons from the lipids, often affecting polyunsaturated fatty acids, in the neural cell membranes (lipid peroxidation), resulting in degradation and peroxidation of lipids and cell damage. In addition, some end-products of lipid peroxidation, such as malondialdehyde, are mutagenic and carcinogenic (Nair et al. 2007). Furthermore, ROS can damage DNA, most readily at guanine residues, which causes mutations resulting in inheritable disease, cancer and aging (Cadet et al. 2003). In the past decades, these processes of oxidative damage have been well characterized in a large variety of diseases including neurological disorders .

As stated in Chap. 1, exercise is defined as any planned structured activity, which leads to increase in energy expenditure and heart rate . Exercise is classified by the type, intensity, and duration of activity. There are different types of exercises in relation to intensity: (a) aerobic exercise is performed through using equipments, such as treadmill and bicycle or jogging, (b) Yoga, ancient Indian exercise, which involves physical postures, rhythmic stretching movements and regulated breathing, and (c) Tai Chi, ancient Chinese tradition that involves a series of movements performed in a slow, focused manner along with deep breathing. The aerobic metabolism primarily generates energy from fat, and with the use of oxygen it produces energy, without much accumulation of lactic acid in the blood. Yoga and Tai Chi are particularly useful for promoting flexibility of core muscles, maintenance of balance and fall prevention through induction of antidepressant-like effects such as modulation of neurotransmitter level, elevation in BDNF levels, and boosting serotonin along with reduction in inflammation, oxidative stress, blood levels of lipids and growth factors (Yang 2007; Saeed et al. 2010; Bussing et al. 2012). All types of exercises result in increased blood flow, hormesis , and mitochondrial biogenesis (Fig. 10.3). Thus, regular moderate physical exercise has been shown to produce many beneficial effects on the human health including marked decrease in mortality along with a reduced risk of developing cardiovascular and cerebrovascular diseases, neurological disorders, cancer, and diabetes (Blair et al. 2001; Oguma et al. 2002; Farooqui 2013) . Exercise produces cardiovascular and cerebrovascular changes and muscular fitness by elevating energy consumption, improving insulin sensitivity, increasing blood flow, strengthening the immune system, reducing inflammation, promoting sleep, and controlling weight. The molecular mechanisms underlying above mentioned processes are not fully understood. However, it is becoming increasingly evident that exercise not only improves the dyslipidemic profile by raising high density lipoprotein-cholesterol and lowering triglycerides in the body (Lakka and Laaksonen 2007), but also increases expression of GLUT4 and other proteins involved in insulin signaling and glucose metabolism (Houmard et al. 1993).

Both resting and contracting skeletal muscles produce low levels of ROS and RNS through the involvement of mitochondria, NADPH oxidase, PLA₂-dependent processes, xanthine oxidase, and increased expression of myokines (proteins secreted from skeletal muscle cells). Myokines include IL-6, IL-15, irisin, BDNF, MCP-1, ANGPTL-4, FGF-21, erythropoietin, and myonectin (Raschke and Eckel 2013). It is suggested that contraction-regulated myokines play a pivotal role in the communication between muscle and other tissues such as adipose tissue, liver, and pancreatic cells through the involvement of STAT, MAPK, PtdIns 3K/Akt and NF-κB signaling pathways (Pedersen 2011; Pedersen and Febraio 2008; Raschke and Eckel 2013). It is interesting to note that among above mentioned myokines, FNDC5, BDNFmRNA, erythropoietin-R mRNA, and their protein expression are increased in human skeletal muscle after exercise; however, muscle-derived BDNF and erythropoitin are not released into the circulation (Matthew et al. 2009). In muscle cells, BDNF not only increases phosphorylation of AMP kinase (AMPK) and Acetyl CoA Carboxylase (ACC), but enhances oxidation of fat both in vitro and ex vivo. In contrast, results on the involvement of erythropoietin have been inconsistent and inconclusive (Lamon and Russell 2013). AMPK is a key factor involved in modulation of exercise-mediated increase in fast-to-slow transition, a process that increases the proportion of oxidative fibers in the muscles (Narkar et al. 2008). AMPK is a heterotrimeric serine-threonine kinase, which consists of the catalytic α subunit (α1, α2), scaffolding β subunit (β1, β2) and nucleotide-binding γ subunit (γ1, γ2, γ3) (Steinberg and Kemp 2009). AMPK senses the AMP/ATP ratio via AMP binding to its γ subunit; AMP binding induces α subunit phosphorylation on Thr172 by AMPK kinases. Thr172 phosphorylation activates AMPK (Jensen et al. 2009). AMPK activation is associated with increased mitochondrial enzyme content and mitochondrial biogenesis in rat skeletal muscle. AMPK is activated by a low ATP/AMP ratio, and it has been proposed to serve as a fuel gauge for mammalian cells to protect against energy deprivation (Harding and Carling 1997). Acute activation of this enzyme in muscle helps defend against energy deficiency by promoting increased glucose transport and fatty acid oxidation through increased GLUT4 translocation (Bergeron et al. 2001) and inhibition of acetyl CoA carboxylase respectively (Atkinson et al. 2002). Mice lacking both AMPK β isoforms in skeletal muscles have drastically reduced exercise capacity, muscle mitochondria content and contraction-stimulated glucose uptake (O’Neil et al. 2011).

Recent studies have indicated that moderate exercise-mediated mild oxidative stress reversibly control the expression of at least 127 genes and signal transducing proteins reported to be not only sensitive to reductive and oxidative (redox) states in the cell (Allen and Tresini 2000; Frein et al. 2005), but also to gap junctional intercellular communication, which plays a role in coordinating gene expression between cells of a tissue needed to maintain cellular and tissue homeostasis (Upham and Trosko 2009). Moderate exercise-mediated changes in genes expression of skeletal muscles include alterations in expression of antioxidant enzymes, stress proteins, DNA repair proteins, and mitochondrial electron transport proteins (Allen et al. 2008; Powers and Jackson 2008). These proteins not only promote repair after injury, but also facilitate permanent beneficial adaptations, which may include increase in activators of mitochondrial biogenesis, such as the transcriptional coactivator peroxisome proliferator-activated receptor γ co-activator 1-α (PGC-1α) and increase in activity of oxidative enzymes such as citrate synthase and succinate dehydrogenase (Carter et al. 2001; Fernstrom and Fernstrom 2006). The molecular mechanisms that link PGC-1α with the control of ROS production remains unknown. However, it is known that PGC-1α activity is regulated by a variety of post-translational modifications including phosphsphorylation, acetylation, methylation and ubiquination (Jager et al. 2007; Rodgers et al. 2008; Dominy et al. 2010). Thus in neural (brain and spinal cord) and non-neural tissues (liver and muscles), PGC-1α is phosphorylated by p38 MAPK and AMPK at a variety of amino acid residues, which result in a more stable and active PGC-1α protein. The acetylase transferase (GCN5) acetylates PGC-1α at several lysine residues to inactivate PGC-1α while the NAD ⁺-dependent deacetylase, sirtuin 1 (SIRT 1) removes acetyl groups leading to activation of PGC-1α (Fig. 10.4). SIRTs belong to Class III histone deacetylases, which regulate epigenetic gene silencing and suppress recombination of rDNA (Yamamoto et al. 2007). In mammals, SIRTs have a range of molecular functions and have emerged as important proteins in aging and metabolic regulations (Yamamoto et al. 2007; Rajendran et al. 2011). SIRTs represent a small gene family with seven members designated as SIRT1–7, known to be modulated by oxidative stress (Yamamoto et al. 2007; Rajendran et al. 2011) . Accumulating evidence suggests that post-translational modifications activate and/or deactivate PGC-1α located in the nucleus or within the cytosol of the cell. Recent studies have also indicated that moderate exercise activates a cytosolic pool of PGC-1α and promotes its migration to the nucleus, where it initiates mitochondrial gene expression prior to increase in overall PGC-1α expression. Thus, post-translational modifications represent an immediate mechanism to activate PGC-1α and initiate PGC-1α-dependent gene expression (Wright et al. 2007). PGC-1α has a powerful suppressive effect on ROS production, in parallel to its effects in elevating mitochondrial respiration. This occurs through the PGC-1α-mediated expression of genes involved in ROS detoxification, as well as the expression of uncoupling proteins that can attenuate ROS production (St-Pierre et al. 2006; Valle et al. 2005). In addition, heat shock proteins (Hsps), which are induced under oxidative stress, promote the production of anti-inflammatory cytokines, indicating immunoregulatory potential of these proteins. Therefore, the presence of immune responses to Hsps in inflammatory diseases is considered as an attempt of the immune system to correct the inflammatory condition (Lakka and Laaksonen 2007; Morton et al. 2009). It is also proposed that exercise boosts the production of human growth hormone and blocks maladaptive pathways, which may not only provide protection against protein misfolding diseases, but also promote preservation of muscle function during aging (Morton et al. 2009). Recent studies have also indicated that human genome contains genes controlling either the motivation or ability to exercise (Good et al. 2008). Collective evidence suggests that exercise-mediated production of low levels of ROS plays an important physiological function in the regulation of both muscle force production and contraction-induced adaptive responses of muscle fibers . These processes not only involve the participation of myokine-mediated signal transduction pathways, but also mediate changes (a) transcriptional regulation of nuclear-encoded genes encoding mitochondrial proteins by the PGC-1, (b) control of mitochondrial DNA gene expression by the transcription factor Tfam, (c) mitochondrial fission and fusion mechanisms, and (d) import of nuclear-derived gene products into the mitochondrion via the protein import machinery. Exercise can modify the rates of various steps involved in the biogenesis of mitochondria. Muscle mitochondrial biogenesis involves the assembly of an interconnected network system (mitochondrial reticulum). This expansion of membrane size is modulated by the balance between mitochondrial fusion and fission. Accumulating evidence suggests that mitochondrial biogenesis is an adaptive mechanism, which requires the coordination of multiple cellular events, including the transcription of two genomes, the synthesis of lipids and proteins and the stoichiometric assembly of multisubunit protein complexes into a functional respiratory chain. Impairment at any step may not only cause defective electron transport, but also result in a subsequent failure of ATP synthesis, leading to an inability to maintain redox potential and energy homeostasis (Hood et al. 2006) .

In contrast, intense and prolonged exercise results in high ROS and RNS-mediated oxidative damage to both proteins, release of excess of cortisol , and lipid degradation in the contracting myocytes. It is suggested that high levels of ROS and RNS promote contractile dysfunction resulting in muscle weakness and fatigue (Fig. 10.5). The molecular mechanisms associated with muscle contractile dysfunction are not fully understood. However, it is becoming increasingly evident that high levels of oxidants (ROS and RNS) along with high levels of cortisol may alter cell signaling pathways, which are closely associated with contractile dysfunction. Thus, ROS and RNS have been reported to modulate a number of cell signaling pathways as well as regulate the expression of multiple genes in eukaryotic cells (Allen et al. 2008; Powers and Jackson 2008). ROS and RNS-mediated changes in gene expression not only involve changes at transcriptional level and stability of mRNA, but also intensity of signal transduction processes involved in muscle contraction leading to fatigue and microscopic tears in the skeletal muscles, increase in inflammation in lining of arteries, and sudden cardiac fatigue promoted by increase in catecholamines and adrenalin, which may trigger arrhythmia and cardiac arrest (Fig. 10.6) . One common arrhythmia is atrial fibrillation, commonly known as “A-fib”. A-fib is epidemic among endurance athletes, which sets them up for major increase in stroke risk. Marathoners above age 50 have a five-fold increase in A-fib rates (O’Keefe et al. 2012) supporting the view that high intensity running is harmful for human health. High levels of cortisol may not only promote weight gain (visceral obesity) and sleeping problems, but may also induce obesity (weight gain). Some studies have shown that elevated cortisol levels tend to cause fat deposition in the abdominal area rather than in the hips (Tchernof and Despres 2013). This fat deposition has been referred to as “toxic fat” since abdominal fat deposition is strongly correlated with the development of cardiovascular disease including heart disease and strokes (Farooqui 2013) .

Moderate physical exercise is known to produce preventive and therapeutic effects in neurological disorders (Deslandes et al. 2009; Wichi et al. 2009) . The neuroprotective effect of exercise can be explained by the hormesis, which is defined as a biphasic dose response whereby moderate exercise stimulates resistance to stress and improves biological fitness, while too much exercise induces damage and inhibits function. This concept of hormesis can be extended to the effect of exercise on ROS and RNS production in muscles (Radak et al. 2005; Radak et al. 2008). ROS and RNS generated during exercise can cause oxidative and nitrosative stress and damage to skeletal muscle, heart muscle, and muscles of other organs, and neurochemical changes in the brain. It is well known that at low levels ROS and RNS serve as the chemical agents (mediators) for maintaining cellular milieu and transferring messages from one subcellular organelle to another to conduct physiological functions, such as contraction, bioenergetics, growth, proliferation and remodeling (adaptation). The preventive and therapeutic effects of regular exercise, at least in part, can be explained by ROS and RNS-mediated adaptation. The oxidative challenge-related adaptive processes regulated by exercise do not just depend upon the production of ROS and RNS but also on the increase in antioxidant and housekeeping enzyme activities, which are associated with modulation of the oxidative damage repairing enzymes. Thus, moderate exercise-induced ROS and RNS production plays an important role in the induction of antioxidants, induction of Hsps, DNA repair, and protein-degrading enzymes and significantly reduce incidence of oxidative stress induced by the disease. Exercise also mediates it effects by increasing the circulation of same proinflammatory cytokines (myokinase) that are normally upregulated during a mild stress response. However, as stated above, exercise may also upregulate the expression of anti-inflammatory cytokines, which inhibit inflammation and with time increase the immune system threshold for stress (Zaldivar et al. 2006). Studies on RNAs from rodents exposed to a running wheel for 3, 7 and 28 days using a microarray indicate that exercise mediates the expression of 1176 cDNAs in the brain (Molteni et al. 2002) . Quantification of selected genes by Taqman RT-PCR or RNase protection assay indicates the onset of up-regulation of genes associated with synaptic trafficking (synapsin I, synaptotagmin and syntaxin); signal transduction pathways (Ca^2 + /calmodulin-dependent protein kinase II, CaM-KII; mitogen-activated/extracellular signal-regulated protein kinase, MAP-K/ERK I and II; protein kinase C, PKC-delta) or transcription regulators (cyclic AMP response element binding protein, CREB) (Molteni et al. 2002). In addition, genes associated with the glutamatergic neurotransmission (N-methyl-d-aspartate receptor, NMDAR-2A and NMDAR-2B and excitatory amino acid carrier 1, EAAC1) are also up-regulated, while genes related to the gamma-aminobutyric acid (GABA) neurotransmission are down-regulated (GABAA receptor, glutamate decarboxylase GAD65). The temporal profile of exercise-mediated gene expression delineates a mechanism by which specific molecular pathways are activated after exercise performance. For example, the CaM-K signal system is turned on and activated during acute and chronic periods of exercise, while the MAP-K/ERK system play an important role moderate during long-term exercise sessions (Molteni et al. 2002). At the molecular level moderate exercise initiates and stimulates intracellular programs that not only upregulate antioxidant systems (copper–zinc (CuZn) and manganese (Mn) superoxide dismutase (SOD1 and SOD2, respectively), which facilitate repair, but also promotes mitochondrial biogenesis. Several transcription factors, enzymes, and chaprone proteins such as nuclear factor erythroid 2-related factor 1/2 (Nrf-1/2), PPAR γ coactivator 1 (PGC-1), forkhead transcription factors (FOXO), sirtuins, AMPK, mitochondrial transcription factor A (Tfam) and Hsps contribute to the beneficial effects of exercise (Figs. 10.7 and 10.8) (Calabresse et al. 2010; Sano and Fukuda 2008; Son et al. 2008). Among these factors, Hsps play an important role in neuroprotection. Hsps are induced via highly regulated signaling cascades, including the three major mitogen-activated protein kinases (MAPK) and protein kinase B (PKB/Akt) (Nadeau and Landry 2007; van Ginneken et al. 2006; Wigmore et al. 2007) . Both these pathways are impacted by exercise (Chen and Russo-Neustadt 2005; Shen et al. 2001). The exercise-mediated alterations in MAPK element p38 not only upregulate phosphorylation of small heat shock protein (sHsp, mol mass 15–42 kDa) (Ito et al. 2005; Maizels et al. 1998), but also down-regulate pAkt and pERK activities, which may promote dephosphorylation in HSF1-ser307 leading to stabilization of its activity (Seo et al. 2006; Wigmore et al. 2007). Based on this information, it is suggested that voluntary moderate exercise upregulates the small heat shock proteins Hsp27 and produces elevation in the pre-synaptic and SNAP-25 and the post-synaptic protein PSD95, which coincides with the sHsp response (Fig. 10.9). The transport of PSD95 to dendrites through PtdIns 3K-induced Akt signaling is coupled with BDNF-mediated activation of NMDA receptor and influx of Ca^2 + (Yoshii and Constantine-Paton 2007). In addition, exercise also induces immediate early gene (IEG) along with IEGs, which are induced preferentially by depolarization (IPD-IEG) (Machado et al. 2008). These processes not only play an important role in neuroprotection via the production and secretion of BDNF and Hsps (Hu et al. 2009; Vaynman et al. 2004; Vaynman et al. 2006). Exercise also decreases blood pressure by attenuating oxidative stress in the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) of Spontaneously hypertensive rats (SHRs), possibly by reducing sympathoexcitation supporting the view that chronic exercise not only attenuates proinflammatory cytokines and the vasoconstrictor axis of the brain/central renin-angiotensin system (RAS) but also attenuates sympathoexcitation, improves anti-inflammatory defense mechanisms and vasoprotective axis of the RAS in the brain, which, at least in part, explains the blood pressure-lowering effects of exercise in hypertension (Agarwal et al. 2011) .