Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite.

Three types of overlap occur among the disease states chronic fatigue syndrome (CFS), fibromyalgia (FM), multiple chemical sensitivity (MCS) and posttraumatic stress disorder (PTSD). They share common symptoms. Many patients meet the criteria for diagnosis for two or more of these disorders and each disorder appears to be often induced by a relatively short-term stress which is followed by a chronic pathology, suggesting that the stress may act by inducing a self-perpetuating vicious cycle. Such a vicious cycle mechanism has been proposed to explain the etiology of CFS and MCS, based on elevated levels of nitric oxide and its potent oxidant product, peroxynitrite. Six positive feedback loops were proposed to act such that when peroxynitrite levels are elevated, they may remain elevated. The biochemistry involved is not highly tissue-specific, so that variation in symptoms may be explained by a variation in nitric oxide/peroxynitrite tissue distribution. The evidence for the same biochemical mechanism in the etiology of PTSD and FM is discussed here, and while less extensive than in the case of CFS and MCS, it is nevertheless suggestive. Evidence supporting the role of elevated nitric oxide/peroxynitrite in these four disease states is summarized, including induction of nitric oxide by common apparent inducers of these disease states, markers of elevated nitric oxide/peroxynitrite in patients and evidence for an inductive role of elevated nitric oxide in animal models. This theory appears to be the first to provide a mechanistic explanation for the multiple overlaps of these disease states and it also explains the origin of many of their common symptoms and similarity to both Gulf War syndrome and chronic sequelae of carbon monoxide toxicity. This theory suggests multiple studies that should be performed to further test this proposed mechanism. If this mechanism proves central to the etiology of these four conditions, it may also be involved in other conditions of currently obscure etiology and criteria are suggested for identifying such conditions.     

Say NO to fibromyalgia and chronic fatigue syndrome: an alternative and complementary therapy to aerobic exercise

Increased shear stress to the endothelium increases activity of endothelial nitric oxide synthase (eNOS) with subsequent release of small quantities (nMol) of nitric oxide (NO) into the circulation. It occurs during moderate aerobic exercise mostly as a result of laminar shear stress and with whole body, periodic acceleration as a result of pulsatile shear stress. The latter is administered by means of a new, non-invasive, passive exercise device. Moderate exercise has long been known to alleviate the symptoms of fibromyalgia and chronic fatigue syndrome and in the current study, whole body, periodic acceleration did as well. Since NO through action of eNOS has potent anti-inflammatory properties mainly by suppressing nuclear factor kappabeta activity, it is hypothesized that both diseases have chronic inflammation as their basis. Whole body periodic acceleration can be applied separately or supplementary to aerobic exercise in the treatment of fibromyalgia and chronic fatigue syndrome.     

Nitric oxide synthase partial uncoupling as a key switching mechanism for the NO/ONOO- cycle

Short-term stressors, capable of increasing nitric oxide levels, act to initiate cases of illnesses including chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia and posttraumatic stress disorder. These stressors, acting primarily through the nitric oxide product, peroxynitrite, are thought to initiate a complex vicious cycle mechanism, known as the NO/ONOO- cycle that is responsible for chronic illness. The complexity of the NO/ONOO- cycle raises the question as to whether the mechanism that switches on this cycle is this complex cycle itself or whether a simpler mechanism is the primary switch. It is proposed here that the switch involves a combination of two variable switches, the increase of nitric oxide synthase (NOS) activity and the partial uncoupling of the NOS activity, with uncoupling caused by a tetrahydrobiopterin (BH4) deficiency. NOS uncoupling causes the NOS enzymes to produce superoxide, the other precursor of peroxynitrite, in place of nitric oxide. Thus partial uncoupling will cause NOS proteins to act like peroxynitrite synthases, leading, in turn to increased NF-kappaB activity. Peroxynitrite is known to oxidize BH4, and consequently partial uncoupling may initiate a vicious cycle, propagating the partial uncoupling over time. The combination of high NOS activity and BH4 depletion will lead to a potential vicious cycle that may be expected to switch on the larger NO/ONOO- cycle, thus producing the symptoms and signs of chronic illness. The role of peroxynitrite in the NO/ONOO- cycle also implies that such uncoupling is part of the chronic phase cycle mechanism such that agents that lower uncoupling will be useful in treatment.     

Vascular pulsations stimulating nitric oxide release during cyclic exercise may benefit health: a molecular approach (review)

It is widely assumed that all exercise, regardless of the degree of difficulty or strenuousness, is good (no pain-no gain). In this speculative review of the literature and our research findings we highlight the fact that strenuous exercise taken to the extreme initiates an immune and vascular proinflammatory situation. However, mild cyclic exercise appears to produce health benefits for an individual. In part, this is due to vascular cyclic pulsations, occurring in mild exercise, stimulating constitutive nitric oxide synthase derived nitric oxide release. This in turn down-regulates vascular endothelial cells and immunocytes, as well as their interaction and inhibits the disassociation of NF-kappaB, preventing the production of proinflammatory cytokines. The nitric oxide so generated may even scavenge excess free radicals, preventing tissue damage. Prolonged strenuous exercise appears to limit these positive phenomena because of the maintained and prolonged high blood pressure that reduces the cyclic pulsations, limiting nitric oxide production. We further note that pathological conditions, i.e., Parkinson's disorder, may benefit from mild exercise, i.e., cyclic nitric oxide production, since the inactivity associated with this disease may lead to compromised nitric oxide production, initiating a progressive deterioration of tissues, including peripheral adrenergic neurons, due to a lack of adequate basal nitric oxide levels required to maintain the vascular microenvironment in a mild state of inhibition. We conclude that mild exercise represents an alternate and economical therapy to preserve health and/or diminish the rate of decline of the normal physiological processes that may even be associated with aging.     

Muscular effects in late polio.

New or increased muscular weakness, fatigue and muscle and joint pain with neuropathic electromyography (EMG) changes in a person with a confirmed history of polio constitute the cardinal symptoms of the post-polio syndrome. Unusual tiredness or fatigue is a common complaint in late polio subjects as is intolerance to cold. Fatigue in polio subjects can have several explanations: emotional fatigue, central nervous system fatigue, 'general' fatigue and/or neuromuscular fatigue. Some studies indicate central fatigue, but it is unclear how often and to which degree there will be a central muscular fatigue. Polio patients are known to be deconditioned (reduced function because of low activity level), and aerobic power is reduced. Defects in the neuromuscular transmission may be present but are not seen in all post-polio subjects with reduction in force and increased fatigability. The fatigue experienced by late polio patients is most likely an augmented peripheral muscle fatigue. Possible explanations may be an imperfection in the sarcoplasmatic reticulum with altered calcium release mechanisms (activation) or in sliding filament function (contractile properties). This may be a secondary effect to the enlarged muscle fibres. However, the prolonged subjective feeling of fatigue reported despite unchanged maximal voluntary contraction (MVC) remains unexplained.     

Muscular effects in late polio

New or increased muscular weakness, fatigue and muscle and joint pain with neuropathic electromyography (EMG) changes in a person with a confirmed history of polio constitute the cardinal symptoms of the post‐polio syndrome. Unusual tiredness or fatigue is a common complaint in late polio subjects as is intolerance to cold. Fatigue in polio subjects can have several explanations: emotional fatigue, central nervous system fatigue, ‘general’ fatigue and/or neuromuscular fatigue. Some studies indicate central fatigue, but it is unclear how often and to which degree there will be a central muscular fatigue. Polio patients are known to be deconditioned (reduced function because of low activity level), and aerobic power is reduced. Defects in the neuromuscular transmission may be present but are not seen in all post‐polio subjects with reduction in force and increased fatigability. The fatigue experienced by late polio patients is most likely an augmented peripheral muscle fatigue. Possible explanations may be an imperfection in the sarcoplasmatic reticulum with altered calcium release mechanisms (activation) or in sliding filament function (contractile properties). This may be a secondary effect to the enlarged muscle fibres. However, the prolonged subjective feeling of fatigue reported despite unchanged maximal voluntary contraction (MVC) remains unexplained.     

不同模式下血流限制治疗老年性肌肉减少症的效果与安全因素

背景:有研究报道了血流限制疗法对中老年肌肉适能的影响与优势,基本肯定了血流限制疗法应用的科学性和其改善中老年人肌力及肌肉量的有效性,但关于不同运动模式下的血流限制疗法在老年性肌肉减少症中的应用以及相关作用机制的综述国内外还未见报道。目的:综述不同运动模式下的血流限制疗法应用于老年性肌肉减少症的应用效果、安全性及不良反应,为此类患者选择科学有效的治疗方式提供新的思路。方法:在PubMed、ScienceDirect、Web of Science、万方、维普、CNKI数据库检索2005年1月至2020年7月收录的相关文献,英文检索词为“blood flow restriction or exercise or therapy;KAATSU training;sarcopenia;motor function;mechanism”;中文检索词为“血流限制疗法;血流限制训练;血流限制;加压血流阻滞训练;加压训练;老年性肌肉减少症;肌少症;少肌症;肌肉力量;运动功能;机制”,经筛选后对50篇文献进行归纳总结。结果与结论:①在老年性肌肉减少症患者中使用血流限制疗法可增加肌肉力量和肌容积,尤其是与中低强度抗阻运动结合的效果最佳且不良反应少;②血流限制疗法可能通过增加肌肉组织蛋白合成与降解速率、提高线粒体能量代谢水平及改善组织微循环水平发挥作用,但目前血流限制疗法发挥作用的机制仍存在争议,需进一步研究加以论证;③在老年性肌肉减少症患者中使用血流限制疗法尚无明确的安全性结论,使用中需重点关注血流闭塞压力和运动负荷情况。     

Redox modulation of contractile function in respiratory and limb skeletal muscle

For the last half century, scientists have studied the biological importance of free radicals in respiratory and limb muscles. We now know that muscle fibers continually produce both reactive oxygen species (ROS) and nitric oxide (NO) and that both cascades play critical roles in contractile regulation. Under basal conditions, muscle-derived ROS and NO exert opposing effects. Low-level ROS activity is an essential part of the homeostatic milieu and is required for normal force production whereas NO derivatives function as a brake on the system, limiting force. The modulatory effects of ROS and NO are disrupted by conditions that exaggerate production including mechanical unloading, inflammatory disease, and strenuous exercise. Marked increases in ROS or NO levels cause contractile dysfunction, resulting in muscle weakness and fatigue. These principles provide a foundation for ongoing research to identify the mechanisms of ROS and NO action and develop interventions that protect muscle function.     

Skin biopsy findings: implications for the pathophysiology of fibromyalgia

The mechanisms responsible for symptom expression in fibromyalgia (FM) are complex. The most consistently detected objective abnormalities in FM involve pain-processing systems. Up to recently, central nervous system was a primary focus of investigations in FM. Although it is unlikely that FM occurs because of primary disorders of the peripheral tissues, there are still data to suggest that some abnormalities can be detected in the periphery. With the recognition of abnormalities in skin of some FM patients, it is now apparent that the role of peripheral nerve endings in FM is much greater than previously thought. The aim of this paper is to review literature concerning the skin biopsy findings of FM patients and discuss their potential relevance to FM. This paper suggests that patients with FM represent a state of the dysfunction of descending, antinociceptive pathways and low hypothalamic-pituitary-adrenal function. This state is further proposed to result in many skin biopsy findings associated with the disorder, including increased N-methyl-d-aspartate receptors subtype 2D expression, neurogenic inflammation and characteristic electron microscopic findings. Future direction of research would be identification of specific laboratory markers such as skin biopsy for diagnostic and clinical evaluation purposes in FM.     

内源性一氧化氮合酶抑制物上调4周运动大鼠骨骼肌收缩功能和线粒体生物合成

目的:观察内源性一氧化氮合酶(NOS)抑制物非对称性二甲基精氨酸(ADMA)及其信号通路在4周运动大鼠NO水平及骨骼肌收缩功能与线粒体生物合成中的调节作用。方法:建立4周运动大鼠模型,检测离体比目鱼肌对电刺激的单次、强直和疲劳收缩的最大张力;并检测骨骼肌中ATP和线粒体DNA含量以及过氧化物酶增殖体受体γ辅激活因子1α(PGC-1α)、核呼吸因子(NRF)mRNA的表达以反映线粒体生物合成及功能;用高效液相色谱测定血清ADMA浓度;用Western blot法检测骨骼肌中内源性ADMA生成酶PRMT1和ADMA代谢酶DDAH2种亚型以及NOS 3种亚型蛋白的表达;用比色法测定NOS活性及一氧化氮(NO)含量等。结果:与正常对照组相比,运动组大鼠比目鱼肌对电刺激诱导的各种收缩张力均明显增强,比目鱼肌ATP含量、线粒体DNA含量和PGC-1α、NRF mRNA增加显著(P0.01)。运动组大鼠比目鱼肌中构成型NOS(cNOS)的蛋白表达及其NOS活性明显上调(P0.01),而NO含量仅小幅增加(P0.05);同时,4周运动增加大鼠血清ADMA浓度,并伴有骨骼肌DDAH2表达下调。结论:短期耐力运动增强比目鱼肌单次收缩、强直收缩和抗疲劳收缩肌功能,其机制可能与过度增加的cNOS促使ADMA水平反馈性升高,从而维持骨骼肌NO低幅度增加,促进线粒体生物合成有关。     

Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age

The molecular basis underlying the clinical variability in symptomatic Duchenne muscular dystrophy (DMD) carriers are still to be precised. We report 26 cases of early symptomatic DMD carriers followed in the French neuromuscular network. Clinical presentation, muscular histological analysis and type of gene mutation, as well as X-chromosome inactivation (XCI) patterns using DNA extracted from peripheral blood or muscle are detailed. The initial symptoms were significant weakness (88%) or exercise intolerance (27%). Clinical severity varied from a Duchenne-like progression to a very mild Becker-like phenotype. Cardiac dysfunction was present in 19% of the cases. Cognitive impairment was worthy of notice, as 27% of the carriers are concerned. The muscular analysis was always contributive, revealing muscular dystrophy (83%), mosaic in immunostaining (81%) and dystrophin abnormalities in western blot analysis (84%). In all, 73% had exonic deletions or duplications and 27% had point mutations. XCI pattern was biased in 62% of the cases. In conclusion, we report the largest series of manifesting DMD carriers at pediatric age and show that exercise intolerance and cognitive impairment may reveal symptomatic DMD carriers. The complete histological and immunohistological study of the muscle is the key of the diagnosis leading to the dystrophin gene analysis. Our study shows also that cognitive impairment in symptomatic DMD carriers is associated with mutations in the distal part of the DMD gene. XCI study does not fully explain the mechanisms as well as the wide spectrum of clinical phenotype, though a clear correlation between the severity of the phenotype and inactivation bias was observed.     

Central nitric oxide inhibition modifies metabolic adjustments induced by exercise in rats

The influence of the central nervous system on metabolic function is of interest in situations deviating from basal states, such as during exercise. Our previous study in rats demonstrated that central nitric oxide (NO) blockade increases metabolic rate, reducing mechanical efficiency during exercise. To assess the role of brain nitric oxide in the plasma glucose, lactate and free fatty acids (FFAs) concentrations of rats submitted to an incremental exercise protocol on a treadmill until fatigue, 1.43 micromol (2 microl) of N(omega)-nitro-l-arginine methyl ester (L-NAME, n=6), a NO synthase inhibitor, or 2 microl of 0.15M NaCl (SAL, n=6) was injected into the lateral cerebral ventricle (icv) of male Wistar rats immediately before exercise (starting at 10 m/min, with increments of 1m/min every 3 min until fatigue, 10% inclination). Blood samples were collected through a chronic jugular catheter at rest and during exercise until fatigue. During exercise, the L-NAME-treated animals had the following metabolic response compared to controls: (1) an increased hyperglycemic response during the first 60% of time to fatigue; (2) higher plasma lactate levels; and (3) a significant transitory increase in plasma free fatty acids during the dynamic phase of exercise that returned to basal levels earlier than controls during the steady state phase of exercise. In addition L-NAME-treated rats fatigued earlier than controls. The data indicate that the inhibition of the brain nitrergic system induced by icv L-NAME treatment disrupted the accuracy of the neural mechanism that regulates plasma glucose and free fatty acids mobilization during exercise in rats.     

Effects of vitamin E deficiency on fatigue and muscle contractile properties

Radical-mediated oxidative damage of skeletal muscle membranes has been implicated in the fatigue process. Vitamin E (VE) is a major chain breaking antioxidant that has been shown to reduce contraction-mediated oxidative damage. We hypothesized that VE deficiency would adversely affect muscle contractile function, resulting in a more rapid development of muscular fatigue during exercise. To test this postulate, rats were fed either a VE-deficient (EDEF) diet or a control (CON) diet containing VE. Following a 12-week feeding period, animals were anesthetized and mechanically ventilated. Muscle endurance (fatigue) and contractile properties were evaluated using an in situ preparation of the tibialis anterior (TA) muscle. Contractile properties of the TA muscle were determined before and after a fatigue protocol. The muscle fatigue protocol consisted of 60 min of repetitive contractions (250 ms trains at 15 Hz; duty cycle=11%) of the TA muscle. Prior to the fatigue protocol, no significant differences existed in the force-frequency curves between EDEF and CON animals. At the completion of the fatigue protocol, muscular force production was significantly (P<0.05) lower in the EDEF group (reduced by 69%) compared to CON group (reduced by 38%). Following the fatigue protocol, a right shift existed in the force-frequency curve at low stimulation frequencies (≤40 Hz) in the EDEF animals compared to the CON animals (P<0.05). The stimulated and the contralateral TA muscle from the EDEF animals had significantly higher markers of lipid peroxidation compared to the same muscles in the CON animals (P<0.05). These data support the hypothesis that VE deficiency impairs muscular endurance and alters muscle contractile properties following a prolonged series of contractions. Electronic Publication     

Inducible and endothelial nitric oxide synthase expression in human atherogenesis: an immunohistochemical and ultrastructural study

BackgroundNitric oxide has been proven to play an important role in the maintenance of vascular tone and structure. Impairment of nitric oxide production is an early indicator of atherosclerosis, but not much is known about the real mechanisms underlying this phenomenon.MethodsIn the present study, immunocytochemical methods have been used to analyze the patterns of expression of endothelial nitric oxide synthase and inducible nitric oxide synthase proteins in healthy and atherosclerotic human aortae using both confocal laser scanning microscopy and electron microscopy.ResultsInduction of the expression of endothelial nitric oxide synthase and inducible nitric oxide synthase proteins was observed in smooth muscle cells of atherosclerotic human aortae. Altered nitric oxide synthase expression was reported in atheromatous plaques and in apparently normal vascular tissues adjacent to the lesions.ConclusionsOur data confirm and extend previous findings of a direct relationship between dysregulation of nitric oxide pathway and atherosclerosis, suggesting another possible mechanism by which nitric oxide synthase system abnormalities may promote vascular dysfunction during human atherogenesis. Changes in nitric oxide production might be the primary step in the development of atheroma.     

Comorbid somatic symptoms and functional status in patients with fibromyalgia and chronic fatigue syndrome: sensory amplification as a common mechanism

BACKGROUND: Somatic symptoms are common in conditions such as fibromyalgia (FM) and chronic fatigue syndrome (CFS). OBJECTIVE: Authors investigated a potential shared pathologic mechanism: a generalized perceptual abnormality where there is heightened responsiveness to varied sensory stimulation, including pain. METHOD: A composite measure of sensory sensitivity was created and compared with measures of somatic symptoms, comorbid psychological disturbances, and self-reported physical functioning in 38 patients with FM and/or CFS. RESULTS: Sensory amplification influenced physical functioning indirectly through pain intensity, and physical symptoms and fatigue also independently contributed to physical functioning. CONCLUSION: Sensory amplification may be an underlying pathophysiologic mechanism in these disorders that is relatively independent of depression and depressive symptoms.     

Sarcolemmal damage in dystrophin deficiency is modulated by synergistic interactions between mechanical and oxidative/nitrosative stresses

Dystrophin deficiency is the cause of Duchenne muscular dystrophy, but the precise physiological basis for muscle necrosis remains unclear. To determine whether dystrophin-deficient muscles are abnormally susceptible to oxidative and nitric oxide (NO)-driven tissue stress, a hindlimb ischemia/reperfusion (I/R) model was used. Dystrophic mdx mice exhibited abnormally high levels of lipid peroxidation and protein nitration, which were preceded by exaggerated NO production during ischemia. Visualization of NO with the fluorescent probe 4,5-diaminofluorescein diacetate suggested that excess NO production during ischemia occurred within a subset of mdx fibers. In mdx muscles only, prior exposure to I/R dramatically increased the level of sarcolemmal damage resulting from stretch-mediated mechanical stress, indicating greatly exacerbated hyperfragility of the dystrophic fiber membrane. Treatment with NO synthase inhibitors (l-N(G)-nitroarginine methyl ester hydrochloride or 7-nitroindazol) effectively blocked the synergistic interaction between I/R and mechanical stress-mediated sarcolemmal damage under these conditions. Taken together, our findings provide direct ex-perimental evidence that several prevailing hy-potheses regarding the cause of muscle fiber damage in dystrophin-deficient muscle can be integrated into a common pathophysiological framework involving interactions between oxidative stress, ab-normal NO regulation, and hyperfragility of the sarcolemma.