Journal of IiME Volume 2 Issue 2 www.investinme.org The Physiology of Exercise Intolerance in Patients with Myalgic Eencephalomyelitis (ME) and the Utility of Graded Exercise Therapy dysfunctional immune system impaired by viral infection. Indeed, a hallmark of ME is a range of symptoms, varying in extent between patients, suggesting that a range of functions are impaired to greater or lesser degrees. ME typically follows a flu-like illness, with elevated concentrations of viral particles subsequently detectable in blood and muscle tissues12. Post-viral fatigue is a well established possible consequence of infection by a range of different viruses13-17, with enteroviruses specifically implicated in the case of ME – elevated concentrations of viral RNA sequences resembling coxsachie virus B are detectable in muscle tissue12. Furthermore, the majority of the limited number of ME patients so far treated with antiviral drugs (interferons) were able to return to work following treatment18, also suggestive of a persistent ‘smoldering infection’19. Crucially, post-viral fatigue is not related to the muscle disuse and deconditioning that can result from the initial period of illness12. Indeed, the mechanism underpinning postviral fatigue is a multifaceted physiological imbalance. Nijs and co-workers20 found that, for ME patients, graded exercise resulted in faulty regulation of the immune system, specifically increased activity of the enzymes “elastase” and “RNase L”. RNase L is a key component in the cell’s virus detection system and is up-regulated in response to viral infection. However, elastase degrades RNase L and is normally involved in removing it from the cell when concentrations are too high. Why should both be highly expressed in ME patients? Elastase is activated and degrades the RNase L in the absence of metabolic regulators such as glutathione. (Glutathione is an amino acid complex that modifies enzyme activity throughout the body, and ME patients exhibit either lower concentrations or an imbalance between its active and inactive forms21-23.) Thus the simultaneous overactivation and mis-regulation of this part of Invest in ME (Charity Nr. 1114035) the immune system can be explained by glutathione depletion. A range of factors contribute to glutathione depletion in the general population, including infection, the oxidative stress induced by strenuous or sustained exercise, and the long-term elevation of the stress hormones cortisol and adrenalin24. Furthermore, glutathione is also involved in sustaining respiration (i.e. the production of chemical energy compounds such as ATP in the mitochondria) thereby providing energy for active tissues such as muscle. Thus muscle tissue effectively competes with the immune system for glutathione25 – sustained physical activity reduces the amount of glutathione available to the immune system, resulting in immune dysfunction. Conversely, an overactive immune system reduces the amount of energy available for muscle tissue, also exacerbating oxidative stress, and can account for both the chronic fatigue and pain (by inducing lactic acid production) that characterise ME. Thus, following an initial period of stress, glutathione concentrations may be too low for the optimal function of both the immune system and muscle tissues, paving the way for both persistent viral infection and fatigue, both of which feedback from each other to render the condition chronic. This situation is compounded by the fact that glutathione not only has a supporting role in the immune response but also directly inhibits the replication of enteroviruses by blocking the formation of one particular protein (glycoprotein B) shared by all – including coxsachie viruses. Indeed, glutathione concentration is a major factor influencing the expression of other persistent viral infections such as HIV26-29. Thus glutathione depletion not only suppresses the immune system, it leaves the body particularly defenceless against enteroviruses. Sustained exercise or stress can deplete glutathione (continued on page 57) Page 56/74
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