**2. Oxidative stress**

**1. Introduction**

14 Discussions of Unusual Topics in Fibromyalgia

**1.1. Fibromyalgia**

**1.2. Etiology**

Fibromyalgia (FM) is a syndrome characterized by generalized pain, muscle rigidity, poor quality of sleep, fatigue, cognitive dysfunction, anxiety, episodes of depression, overall sensitivity, and deterioration in the performance of day-to-day activities [1, 2]. The incidence of FM is higher in women than in men in all decades of life, and it generally appears between 30 and 35 years of age [3, 4]. The prevalence of FM increases with age, reaching a maximum peak around the seventh decade. Fibromyalgia affects about 5% of the population worldwide [5]. According to the classification of the American College of Rheumatology, the definition of FM encompasses two variables: (a) bilateral pain above and below the waist with centralized pain and (b) chronic generalized pain for 3 months with pain on palpation in at least 11 of 18 specific body sites (sensitive spots) [6]. In the presentation of FM alterations to the central and autonomous nervous system, and alterations to the neurotransmitters, hormones, the external immune system, psychiatric conditions, and stress factors are involved [7]. Along with pain there are frequent disturbances in sleep, fatigue, morning rigidity, a subjective sensation of the accumulation of bodily fluids, paresthesias of the extremities, depression, headache, dizziness, and intestinal disturbances, which cause a decrease in quality of life [8]. The current review describes the oxidative stress, mitochondrial alterations, autophagy, antioxidants, and

The etiology and the pathophysiological mechanisms of FM are still unknown and continue to be a challenging clinical entity for researchers and clinicians [9]. Some studies suggest that the involvement of the hypothalamus-pituitary–adrenal axis and the autonomic nervous system in response to stress is present in patients who are vulnerable to suffering with FM or its symptoms [10]. Neuroendocrine factors, anomalies of the autonomic nervous system, genetic characteristics, environmental changes, psychosocial changes, and oxidative stress are involved in the pathophysiology of FM [11]. There is a high prevalence of FM among relatives of patients who also suffer from it, which is attributed to the combination of environmental and genetic factors [12]. Genetic studies suggest that the association with polymorphisms of the serotoninergic, dopaminergic, and catecholaminergic pathways found is implicated in the transmission and modulation of pain [11]. One theory of etiology suggests that infections are capable of activating inflammatory cytokines that could modify the central and peripheral perception of pain in FM. FM is characterized by chronic pain of unknown origin. Evidence suggests that sensitized neurons in the spinal cord of the dorsal horn are responsible for processing increased pain from peripheral nociceptive signals, glial activation, apparently by cytokines and excitatory amino acids that could play a role in the initiation and perpetuation of the pain due to acute or repetitive tissue injury [13]. Three FM subgroups have been described based on the predominant symptoms, depending on the following domains: psychosocial (depression/anxiety), cognitive (catastrophic/pain control), and neurobiology (sensitivity) [14]. The proportion of new patients with FM varies between

alternatives to the pharmacological management of FM.

Oxygen is used by the eukaryotic cells for metabolic transformations and the production of energy by the mitochondria. Under physiologic conditions, there is a beneficial endogenous production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that interact as signaling molecules in multiple physiological mechanisms (**Figure 1**). The ROS have bactericide activity of the phagocytes, act in the transduction of signals, and in the regulation of cellular growth and the redox state of the cell, among other mechanisms [17]. When the ROS or RNS are produced in excess or are not eliminated by the antioxidants, the oxidative stress with the capacity to damage the macromolecules (carbohydrates, proteins, lipids, DNA, and organelles) is produced [18, 19]. In relation to FM, it is important to mention that the cells of the central nervous system are highly vulnerable to the toxic effects of free radicals when

**Figure 1. Formation of reactive oxygen and nitrogen species in mitochondria.** The process is mediated by oxidative phosphorylation and the activity of the mitochondrial NO synthase: In physiological conditions, the production of ROS and RNS is reduced by multiple enzymatic scavengers that involved SOD, GPx, and catalase. When the mitochondria suffer an insult, the increase of the leakage of electrons to the matrix leads to an overload to the capacity of the enzymatic systems and leads to toxicity of the cell. Vectors of reactions and products. The physiological pathway for formation of oxidative stress. Leakage of electron to matrix. Pathophysiological pathway for formation of ROS and RNS.

compared to other organs in the body because they have a high index of oxidative metabolic activity and a low level of protector antioxidant enzymes, with an anatomical neuronal network that is vulnerable to interruption and high concentrations of polyunsaturated fatty acids of the membrane that are easily oxidized [20]. One of the primary enzyme sources of the superoxide anion (O2.−) is the xanthine oxidase. The purine nucleotides are degraded where the phosphate group is lost by the action of the 5′-nucleotidase. The adenosine is deaminated to inosine by the adenosine deaminase (ADA). The inosine is hydrolyzed to produce the purine base hypoxanthine, which is subsequently oxidized to xanthine and later to uric acid by the xanthine oxidase. The xanthine oxidase is an important enzyme that contains iron and molybdenum. The enzyme exists primarily in the form of xanthine dehydrogenase and can convert into xanthine oxidase through diverse conditions including proteolysis, homogenization, and the oxidation of sulfhydryl [21]. Oxidative stress appears to be involved in the severity of symptoms in FM; thus, the antioxidant therapy should be investigated as a possible alternative to adjunct management of FM. Blockage of the production of ROS by the mitochondria offers a new therapeutic strategy to diminish the symptoms of FM and other inflammatory states.

#### **2.1. Lipoperoxides in fibromyalgia**

The overproduction of ROS favors lipid peroxidation (LPO) that leads to the oxidative destruction of the polyunsaturated fatty acids, components of the cellular membranes, and favors the production of cytotoxic metabolites and aldehyde reactives [malondialdehyde (MDA) and 4-hydroxynonenal (HNE)] [22]. The MDA and HNE produced in relatively large quantities have an important capacity for diffusion from their site of origin and attack distant objects to form covalent bonds with diverse molecules [23]. Measuring MDA is one popular method in the search for LPO in bodily fluids or cell lysates. In one study reported in 2011, the authors found increased levels of LPO in mononuclear cells associated with the plasma levels of LPO and clinical symptoms of FM, within the pathophysiology of FM [24]. Research in LPO is highly important since the deleterious effects of oxidative stress could be prevented through control of the underlying pathology and the administration of antioxidants or free radical scavengers.

potentiated or inhibited by the NO donors [29]. In addition, a decrease in capillary volume of the blood vessels, structural disorganization of the capillary endothelium, and structural abnormalities of the mitochondria in histopathology studies of muscles have been reported in FM [30]. The structural damages can contribute to poor oxygen diffusion, less oxidative phosphorylation, and a decrease in the synthesis of ATP, which can increase oxidative stress and LPO of the membrane [31]. Abnormal microcirculation of the skin above sensitive spots in patients with FM has been reported with the use of the laser Doppler flowmetry technique [32]. The results support that local hypoxia and the possible decrease in concentrations of high-energy phosphate result in oxidative stress and LPO of the membrane. Therefore, abnormal microcirculation can be a result of the abnormal regulation of capillary blood flow [33].

**Figure 2. Mechanisms involved in the presentation of fibromyalgia.** The alterations involved in the presentation of fibromyalgia. The etiology and symptomatology of the appearance of fibromyalgia and events may be the cause or

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Mitochondrial myopathies are disturbances that are characterized by morphological anomalies of the mitochondria in muscles. Mitochondrial problems are found in the most common inherited metabolic illnesses. The patients who suffer from mitochondrial myopathies can

**3. Mitochondrial alterations in fibromyalgia**

consequence of having FM.

#### **2.2. Nitric oxide in fibromyalgia**

The production of nitric oxide (NO) occurs from the L-arginine by the nitric oxide synthase (NOS) (**Figure 2**). The NOS has four isoforms: neuronal (nNOS), inducible (iNOS), endothelial (eNOS), and mitochondrial (mtNOS) [25]. The NO is implicated in physiological processes like: vasodilation, modulation of nociception, immune function, neurotransmission, and excitation-contraction coupling [26]. The NO is considered an atypical neurotransmitter and a second messenger in the nervous system [27] or as a hormone [28]. The majority of the effects of NO are mediated through the activation of the guanylate-cyclase enzyme that produces cyclic guanosine-3,5-monophosphate (cGMP) [29]. The NO has pro-nociceptor properties in the neural crest and in the dorsal root ganglia that positively regulate as a result of cutaneous or visceral inflammation and by the peripheral lesions of the fibers. This effect could be The Role of Oxidants/Antioxidants, Mitochondrial Dysfunction, and Autophagy in Fibromyalgia http://dx.doi.org/10.5772/intechopen.70695 17

**Figure 2. Mechanisms involved in the presentation of fibromyalgia.** The alterations involved in the presentation of fibromyalgia. The etiology and symptomatology of the appearance of fibromyalgia and events may be the cause or consequence of having FM.

potentiated or inhibited by the NO donors [29]. In addition, a decrease in capillary volume of the blood vessels, structural disorganization of the capillary endothelium, and structural abnormalities of the mitochondria in histopathology studies of muscles have been reported in FM [30]. The structural damages can contribute to poor oxygen diffusion, less oxidative phosphorylation, and a decrease in the synthesis of ATP, which can increase oxidative stress and LPO of the membrane [31]. Abnormal microcirculation of the skin above sensitive spots in patients with FM has been reported with the use of the laser Doppler flowmetry technique [32]. The results support that local hypoxia and the possible decrease in concentrations of high-energy phosphate result in oxidative stress and LPO of the membrane. Therefore, abnormal microcirculation can be a result of the abnormal regulation of capillary blood flow [33].

#### **3. Mitochondrial alterations in fibromyalgia**

compared to other organs in the body because they have a high index of oxidative metabolic activity and a low level of protector antioxidant enzymes, with an anatomical neuronal network that is vulnerable to interruption and high concentrations of polyunsaturated fatty acids of the membrane that are easily oxidized [20]. One of the primary enzyme sources of the superoxide anion (O2.−) is the xanthine oxidase. The purine nucleotides are degraded where the phosphate group is lost by the action of the 5′-nucleotidase. The adenosine is deaminated to inosine by the adenosine deaminase (ADA). The inosine is hydrolyzed to produce the purine base hypoxanthine, which is subsequently oxidized to xanthine and later to uric acid by the xanthine oxidase. The xanthine oxidase is an important enzyme that contains iron and molybdenum. The enzyme exists primarily in the form of xanthine dehydrogenase and can convert into xanthine oxidase through diverse conditions including proteolysis, homogenization, and the oxidation of sulfhydryl [21]. Oxidative stress appears to be involved in the severity of symptoms in FM; thus, the antioxidant therapy should be investigated as a possible alternative to adjunct management of FM. Blockage of the production of ROS by the mitochondria offers a new therapeutic strategy to diminish the symptoms of FM and other

The overproduction of ROS favors lipid peroxidation (LPO) that leads to the oxidative destruction of the polyunsaturated fatty acids, components of the cellular membranes, and favors the production of cytotoxic metabolites and aldehyde reactives [malondialdehyde (MDA) and 4-hydroxynonenal (HNE)] [22]. The MDA and HNE produced in relatively large quantities have an important capacity for diffusion from their site of origin and attack distant objects to form covalent bonds with diverse molecules [23]. Measuring MDA is one popular method in the search for LPO in bodily fluids or cell lysates. In one study reported in 2011, the authors found increased levels of LPO in mononuclear cells associated with the plasma levels of LPO and clinical symptoms of FM, within the pathophysiology of FM [24]. Research in LPO is highly important since the deleterious effects of oxidative stress could be prevented through control of the underlying pathology and the administration of antioxidants or free

The production of nitric oxide (NO) occurs from the L-arginine by the nitric oxide synthase (NOS) (**Figure 2**). The NOS has four isoforms: neuronal (nNOS), inducible (iNOS), endothelial (eNOS), and mitochondrial (mtNOS) [25]. The NO is implicated in physiological processes like: vasodilation, modulation of nociception, immune function, neurotransmission, and excitation-contraction coupling [26]. The NO is considered an atypical neurotransmitter and a second messenger in the nervous system [27] or as a hormone [28]. The majority of the effects of NO are mediated through the activation of the guanylate-cyclase enzyme that produces cyclic guanosine-3,5-monophosphate (cGMP) [29]. The NO has pro-nociceptor properties in the neural crest and in the dorsal root ganglia that positively regulate as a result of cutaneous or visceral inflammation and by the peripheral lesions of the fibers. This effect could be

inflammatory states.

radical scavengers.

**2.2. Nitric oxide in fibromyalgia**

**2.1. Lipoperoxides in fibromyalgia**

16 Discussions of Unusual Topics in Fibromyalgia

Mitochondrial myopathies are disturbances that are characterized by morphological anomalies of the mitochondria in muscles. Mitochondrial problems are found in the most common inherited metabolic illnesses. The patients who suffer from mitochondrial myopathies can present symptomatology characterized by muscle weakness, pain, fatigue, and exercise intolerance that progressively worsen over time, similar to what happens in patients with FM [34]. Defects in any part of the cycle in the generation of ATP by the mitochondria can alter mitochondrial energy production and cause symptoms [35]. Oxidative stress is implicated in the pathogenesis of FM, which indicates that mitochondrial dysfunction can be associated with FM [36]. In fact, a decrease in the quantity of mitochondrial mass and the coenzyme Q10 (CoQ10) in the production of mitochondrial ROS in mononuclear blood cells has been detected in patients who suffer from FM [37]. Reports of muscle biopsies from the trapezius muscle have shown inflammatory markers, abnormal mitochondria, accumulation of sub-sarcolemma mitochondria, higher incidence of irregular red fibers, and defects of the cytochrome-c oxidase (Complex IV of oxidative phosphorylation) [38]. In addition, the implication of mitochondrial oxidative stress in peripheral nociception described as a predominant symptom mediated by the inflammatory state in FM has been previously reported [39].

**b.** *Microautophagy:* the cytosolic components are absorbed directly by the lysosome through engulfment by the lysosomal membrane. In microautophagy, large structures can also be

The Role of Oxidants/Antioxidants, Mitochondrial Dysfunction, and Autophagy in Fibromyalgia

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**c.** *Chaperone-mediated autophagy:* targeted proteins are translocated through the lysosomal membrane forming a complex with protein chaperones (i.e., Hsc-70) that are recognized by the membrane protein 2A associated with the lysosomes of the lysosomal membrane,

The autophagy mechanism begins with an isolation membrane (phagophore), probably derived from the lipid bilayer originating in the endoplasmic reticulum (ER), and/or through the Golgi apparatus and endosomes [46]. The phagophore expands to engulf intracellular components, isolating protein aggregates, organelles and ribosomes, and forming an autophagosome with a double membrane. The autophagosome matures through fusion with the lysosome, promoting the degradation of the autophagosome content by acidic lysosome proteases. The lysosomal permeases and transporters export amino acids and by-products of degradation to the cytoplasm, where they can be reused for the construction of macromolecules and for metabolism [47]. Selective degradation of the mitochondria mediated by autophagy is called mitophagy [48]. It seems the absence of functional mitochondria produced by metabolic deregulation and autophagy obligates the muscle cells to gain energy without the participation of the Krebs cycle, in comparison to intact mitochondria. The mitochondrial degradation dependent on autophagy or mitophagy is an important process to maintain the critical integrity of the mitochondria and to limit the production of ROS [49]. The deregulation of autophagy and mitochondrial dysfunction could represent key aspects in the pathophysiology of FM [50]. The authors demonstrate that CoQ deficient fibroblasts exhibite increased levels of lysosomal markers (beta-galactosidase, cathepsin, LC3, and Lyso Tracker), and enhanced expression of autophagic genes at both transcriptional and translational levels, indicating the presence of autophagy [51]. CoQ10 deficiency apparently induces autophagy activation in mononuclear blood cells (BMCs) of FM patients by finding increased levels of acid vacuoles in BMCs identified by Lysotracker fluorescence and flow cytometry analysis. The authors suggest restoring mitochondrial functionality with CoQ10 supplementation as demonstrated in *in vitro* studies with decreased lysosomal activity following treatment with CoQ10 [52]. Autophagy is an attractive, strategic target for investigation of bodily fluids or

Treatment for FM is a challenge and often requires nonpharmacological and pharmacological treatment [53]. The dietary habits of FM patients are important, and diverse studies have demonstrated improvement of symptoms with the ingestion of healthy, balanced diets [54]. However, the heterogeneity of symptoms that presents in FM deserves individualized treatment. Therapy should include physiotherapy, psychotherapy, pharmacotherapy, and edu-

ingested through selective and nonselective mechanisms.

causing unfolding and degradation [45].

muscle biopsies in patients who suffer FM (**Figure 2**).

**5. Managing fibromyalgia**

cate the patient on the pathology of FM [55].
