Exercise Intolerance

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An exercise challenge test used for diagnosis.


One of the critical diagnostic criteria for myalgic encephalomyelitis (M.E.) is intolerance of abnormally small amounts of activity or exercise.

By definition, M.E. patients experience “post-exertional relapse” (also sometimes called “post-exertional malaise” or “post-exertional neuroimmune exhaustion”), with their condition getting measurably worse following activity or exercise.

In more severe cases of the illness, relapse can occur for days or weeks following even brief mild activity.

Dozens of studies have looked at this abnormal response to exercise, uncovering numerous physiological abnormalities.

M.E. patients experience abnormally increased inflammation, oxidative stress, C4a complement levels and intramuscular acidosis after exercise. For them, exercise also results in abnormal gene and heat shock protein expression, decreased cerebral oxygenation, lowered mitochondrial ATP, and extended abnormal pH.

Most people get a variety of positive effects from exercise, including increased energy, better sleep and decreased sensitivity to pain.  M.E. patients get the opposite:  increased fatigue, insomnia, higher levels of pain, and other negative symptoms.

Especially in the first years of the illness, M.E. patients often try to be active at a higher level than their bodies can tolerate.  This usually leads to a “push-crash” pattern:  a burst of activity is followed by an extended period of relapse and recovery.

Thus, a challenge for M.E. patients is how to remain even a little active without experiencing repeated “crashes.”

Following is a list (in reverse chronological order) of peer-reviewed articles from medical journals on the phenomenon of exercise intolerance in myalgic encephalomyelitis and the broader condition of chronic fatigue syndrome.

The two-day exercise test discussed in some of these journal articles is now widely accepted as a good diagnostic for ME/CFS and has been helpful in allowing many patients to be approved for disability benefits.


Shukla SK, Cook D, Meyer J, Vernon SD, Le T, Clevidence D, Robertson CE, Schrodi SJ, Yale S, Frank DN. Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). PLoS One. 2015 Dec 18;10(12):e0145453. PMID: 26683192

Following maximal exercise challenge, there was an increase in relative abundance of 6 of the 9 major bacterial phyla/genera in ME/CFS patients from baseline to 72 hours post-exercise compared to only 2 of the 9 phyla/genera in controls (p = 0.005). There was also a significant difference in clearance of specific bacterial phyla from blood following exercise with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls. These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients.


Nijs J, Nees A, Paul L, De Kooning M, Ickmans K, Meeus M, Van Oosterwijck J. Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review. Exerc Immunol Rev. 2014;20:94-116. PMID: 24974723

A literature review suggested that compared to the normal response of the immune system to exercise as seen in healthy subjects, patients with CFS have a more pronounced response in the complement system (i.e. C4a split product levels), oxidative stress system (i.e. enhanced oxidative stress combined with a delayed and reduced anti-oxidant response), and an alteration in the immune cells’ gene expression profile (increases in post-exercise interleukin-10 and toll-like receptor 4 gene expression), but not in circulating pro- or anti-inflammatory cytokines. This provided evidence for an altered immune response to exercise in patients with CFS.


Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment. J Transl Med. 2014 Apr 23;12:104. PMID: 24755065

This study of repeat cardiopulmonary exercise tests showed that ME/CFS participants were unable to reproduce most physiological measures at both maximal and ventilatory threshold intensities during a CPET performed 24 hours after a prior maximal exercise test.


Vermeulen RC, Vermeulen van Eck IW. Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome. J Transl Med. 2014 Jan 23;12:20. PMID: 24456560

Low oxygen uptake by muscle cells was found to cause exercise intolerance in a majority of CFS patients, indicating insufficient metabolic adaptation to incremental exercise. The high increase of the cardiac output relative to the increase of oxygen uptake argued against deconditioning as a cause for physical impairment in these patients.


Learmonth YC, Paul L, McFadyen AK, Marshall-McKenna R, Mattison P, Miller L. McFarlane NG. Short-term effect of aerobic exercise on symptoms in multiple sclerosis and chronic fatigue syndrome: a pilot study. Int J MS Care. 2014 Summer;16(2):76-82. PMID: 25061431

Undertaking 15 minutes of moderate-intensity aerobic cycling exercise had no significant adverse effects on pain or function in people with MS and CFS (with a Karnofsky score of 50-80) within a 24-hour time period.


Snell CR, Stevens SR, Davenport TE, Van Ness JM. Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome. Phys Ther. 2013 Nov;93(11):1484-92. PMID: 23813081

The objective of this study was to determine the discriminative validity of objective measurements obtained during cardiopulmonary exercise testing to distinguish participants with CFS from participants who did not have a disability but were sedentary. The lack of any significant differences between groups for the first exercise test would appear to support a deconditioning hypothesis for CFS symptoms. However, the results from the second test indicated the presence of CFS-related postexertion fatigue.


Strahler J, Fischer S, Nater UM, Ehlert U, Gaab J. Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome. Biol Psychol. 2013 Sep;94(1):160-6. PMID: 23770415

The researchers found evidence of altered sympathetic-neural and sympathetic adrenomedulla reactivity in CFS. Exercise stress revealed a subtle catecholaminergic hyporeactivity in CFS patients.


Kishi A, Togo F, Cook DB, Klapholz M, Yamamoto Y, Rapoport DM, Natelson BH. The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome. Physiol Rep. 2013 Nov;1(6):e00152. PMID: 24400154

Exercise promoted transitions to deeper sleep stages and inhibited transitions to lighter sleep stages for controls and CFS, but CFS also reported increased fatigue and continued to have REM sleep disruption.


Nakamura T, Schwander S, Donnelly R, Cook DB, Ortega F, Togo F, Yamamoto Y, Cherniack NS, Klapholz M, Rapoport D, Natelson BH. Exercise and sleep deprivation do not change cytokine expression levels in patients with chronic fatigue syndrome. Clin Vaccine Immunol. 2013 Nov;20(11):1736-42. PMID: 24027260

The researchers conducted repeat blood sampling for cytokine levels from healthy subjects and CFS patients during both postexercise and total sleep deprivation nights and assayed for protein levels in the blood samples, mRNA activity in peripheral blood lymphocytes (PBLs), and function in resting and stimulated PBLs. They found that these environmental manipulations did not produce clinically significant upregulation of proinflammatory cytokines.


White AT, Light AR, Hughen RW, Vanhaitsma TA, Light KC. Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls. Psychosom Med. 2012 Jan;74(1):46-54. PMID: 22210239

Postexercise mRNA increases in metabolite-detecting receptors were unique to patients with CFS, whereas both patients with MS and patients with CFS showed abnormal increases in adrenergic receptors. Among patients with MS, greater fatigue was correlated with blunted immune marker expression.


Cook DB, Stegner AJ, Nagelkirk PR, Meyer JD, Togo F, Natelson BH. Responses to exercise differ for chronic fatigue syndrome patients with fibromyalgia. Med Sci Sports Exerc. 2012 Jun;44(6):1186-93. PMID: 22157881

The purpose of the present study was to examine cardiac and perceptual responses to steady-state submaximal exercise in CFS patients and healthy controls. The CFS + FM group exhibited an exercise response characterized by higher stroke index, ventilatory equivalents for oxygen and carbon dioxide and rating of perceived exertion, lower systolic blood pressure, and similar HR responses compared to controls.


Jammes Y, Steinberg JG, Delliaux S. Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins. J Intern Med. 2011 Nov 24. PMID: 22112145

The presence of stress factors in the history of CFS patients is associated with severe oxidative stress and the suppression of protective HSP27 and HSP70 responses to exercise.


Jones DE, Hollingsworth KG, Jakovljevic DG, Fattakhova G, Pairman J, Blamire AM, Trenell MI, Newton JL. Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case-control study. Eur J Clin Invest. 2011 Jun 10. PMID: 21749371

CFS patients exhibit “profound abnormality in bioenergetic function.”  When they exercise at the level of normal people, they demonstrate increased intramuscular acidosis that does not decrease normally with repeated exercise.  Compared to normal people, it also takes four times as long for their pH to return to baseline after exercise.


Nijs J, Meeus M, Van Oosterwijck J, Ickmans K, Moorkens G, Hans G, De Clerck LS. In the mind or in the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome. Eur J Clin Invest. 2011 Jul 2. PMID: 21793823

CFS patients suffer from hyperresponsiveness of the central nervous system to various stimuli, including heat, mechanical pressure, electrical stimulation and histamine. Exercise worsens this tendency.


Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC. Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome. J Intern Med. 2011 May 26. PMID: 21615807

CFS patients exhibited two different abnormal responses to exercise.  Some patients demonstrated abnormal increases in mRNA for sensory and adrenergic receptors and a cytokine, resulting in fatigue or pain. A second group demonstrated abnormal decreases in adrenergic α-2A receptor’s transcription. None of the normal patients in the study showed these responses, and the authors thus suggest that this finding has the potential of serving as a biomarker for the disease.


Davenport TE, Stevens SR, Baroni K, Van Ness M, Snell CR. Diagnostic accuracy of symptoms characterising chronic fatigue syndrome. Disabil Rehabil. 2011 Jan 6. PMID: 21208154

Presence of just three measures (fatigue, sleep and pain) was effective in predicting exercise intolerance — a definitional indicator of CFS status.


Vermeulen RC, Kurk RM, Visser FC, Sluiter W, Scholte HR. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. J Transl Med. 2010 Oct 11;8:93.

CFS patients reached the anaerobic threshold and the maximal exercise at a much lower oxygen consumption than the controls, and this worsened in the second test. This implies an increase of lactate, the product of anaerobic glycolysis, and a decrease of the mitochondrial ATP production in the patients.


Meeus M, Ickmans K, De Clerck LS, Moorkens G, Hans G, Grosemans S, Nijs J. Serotonergic descending inhibition in chronic pain: design, preliminary results and early cessation of a randomized controlled trial. In Vivo. 2011 Nov-Dec;25(6):1019-25. PMID: 22021700

The authors administered the antidepressant citalopram to CFS patients and then had them perform a submaximal exercise protocol, preceded and followed by an assessment of endogenous pain inhibition. Significant negative effects were observed in all patients and the authors decided that proceeding with the study would be unethical.


Meeus M, Roussel NA, Truijen S, Nijs J. Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: an experimental study. J Rehabil Med. 2010 Oct;42(9):884-90. PMID: 20878051

CFS patients show hyperalgesia and abnormal central pain processing during submaximal aerobic exercise.


Meeus M, van Eupen I, van Baarle E, De Boeck V, Luyckx A, Kos D, Nijs J. Symptom fluctuations and daily physical activity in patients with chronic fatigue syndrome: a case-control study. Arch Phys Med Rehabil. 2011 Nov;92(11):1820-6. PMID: 22032215

The more that patients with CFS are sedentary and the better activity is dispersed, the fewer symptoms and variations they experience on the same and next day. Inversely, more symptoms and variability is experienced when patients were more active that day or the previous day.


Suárez A, Guillamo E, Roig T, Blázquez A, Alegre J, Bermúdez J, Ventura JL, García-Quintana AM, Comella A, Segura R, Javierre C. Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study. J Womens Health (Larchmt). 2010 May 14. PMID: 20469961

CFS patients had a higher increase in nitric oxide metabolites after exercise than did controls.


Nijs J, Van Oosterwijck J, Meeus M, Lambrecht L, Metzger K, Frémont M, Paul L. Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta. J Intern Med. 2010 Apr;267(4):418-35. PMID: 20433584

Following exercise, complement C4a levels go up more in CFS patients than in healthy people.


Maes M, Twisk FN. Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med. 2010 Jun 15;8:35. PMID: 20550693

The authors describe how physiological abnormalities related to inflammatory, immune, oxidative and nitrosative pathways interfere with exercise tolerance in CFS.


Jones DE, Hollingsworth KG, Taylor R, Blamire AM, Newton JL. Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome. J Intern Med. 2010 Apr;267(4):394-401. PMID: 20433583

CFS patients displayed abnormalities in recovery of intramuscular pH, related to autonomic dysfunction, following exercise.


White AT, Light AR, Hughen RW, Bateman L, Martins TB, Hill HR, Light KC. Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome. Psychophysiology. 2010 Mar 4. PMID: 20230500

CFS patients often display negative responses to exercise, as a result of abnormal inflammatory cytokine activity.


Robinson M, Gray SR, Watson MS, Kennedy G, Hill A, Belch JJ, Nimmo MA. Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome. Scand J Med Sci Sports. 2010 Apr;20(2):282-90. PMID: 19422646

CFS patients have higher levels of F(2)-isoprostanes, an indicator of oxidative stress, after exercise.


Van Oosterwijck J, Nijs J, Meeus M, Lefever I, Huybrechts L, Lambrecht L, Paul L. Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an experimental study. J Intern Med. 2010 Sep;268(3):265-78. PMID: 20412374

Healthy subjects are able to tolerate a higher level of pain following exercise, while CFS patients are able to tolerate a lower level of pain following exercise.


Brown M, Khorana N, Jason LA. The role of changes in activity as a function of perceived available and expended energy in nonpharmacological treatment outcomes for ME/CFS. J Clin Psychol. 2010 Oct 25. PMID: 20976708

CFS patients who were within their energy envelope before treatment showed more improvement in physical functioning and fatigue compared with those outside of their energy envelope.


VanNess JM, Stevens SR, Bateman L, Stiles TL, Snell CR. Postexertional malaise in women with chronic fatigue syndrome. J Womens Health (Larchmt). 2010 Feb;19(2):239-44. PMID: 20095909

Following an exercise test, all the normal sedentary controls recovered quickly (within 24-48 hours) while none of the CFS patients did. Symptoms the patients reported after the test included fatigue, light-headedness, muscular/joint pain, cognitive dysfunction, headache, nausea, physical weakness, trembling/instability, insomnia and sore throat/glands.


Light AR, White AT, Hughen RW, Light KC. Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects. J Pain. 2009 Oct;10(10):1099-112. PMID: 19647494

After sustained moderate exercise, CFS patients showed greater increases than control subjects in gene expression for metabolite detecting receptors ASIC3, P2X4, and P2X5, for SNS receptors alpha-2A, beta-1, beta-2, and COMT and IS genes for IL10 and TLR4.  This correlated with an exacerbation in their symptoms.


Twisk FN, Maes M. A review on cognitive behavioral therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett. 2009;30(3):284-99. PMID: 19855350

The authors discuss how the use of exercise therapy in CFS may be harmful to  patients.


Maes M. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry. 2009 Jan;22(1):75-83. PMID: 19127706

The authors review recent findings on inflammatory and oxidative and nitrosative stress (IO&NS) pathways in CFS and suggest that for these patients, exercise can be a trigger factor causing damage.


Sorensen B, Jones JF, Vernon SD, Rajeevan MS. Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome. Mol Med. 2009 Jan-Feb;15(1-2):34-42. PMID: 19015737

Mannan-binding lectin serine protease 2 (MASP2) was higher than normal following exercise in CFS patients, and this seems related to the phenomenon of post-exertional malaise.


Jammes Y, Steinberg JG, Delliaux S, Brégeon F. Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses. J Intern Med. 2009 Aug;266(2):196-206. PMID: 19457057

CFS patients have more severe and longer oxidative stress following exercise, and this may result from delayed and insufficient heat shock proteins protecting the cells.


Paul L, Rafferty D, Marshal R. Physiological cost of walking in those with chronic fatigue syndrome (CFS): a case-control study. Disabil Rehabil. 2009;31(19):1598-604. PMID: 19848558

Compared to controls walking at the same speed, CFS patients had a lower gross and net oxygen uptake and suffered a higher physiological cost.


Maes M, Twisk FN. Chronic fatigue syndrome: la bête noire of the Belgian health care system. Neuro Endocrinol Lett. 2009;30(3):300-11. PMID: 19855351

In case reports, the authors show that Belgian patients who received Graded Exercise Therapy in fact suffered from disorders of the inflammatory/oxidative/nitrosative stress pathways, including intracellular inflammation, an increased translocation of gram-negative enterobacteria (leaky gut), autoimmune reactions and damage by O&NS. They suggest that exercise was inappropriate treatment and recommend policy changes.


Jason L, Benton M, Torres-Harding S, Muldowney K. The impact of energy modulation on physical functioning and fatigue severity among patients with ME/CFS. Patient Educ Couns. 2009 Nov;77(2):237-41. PMID: 19356884

CFS patients who were able to keep their expended energy close to available energy (i.e. were able to stay within their “energy envelope”) experienced significant improvements in physical functioning and fatigue severity.


Weinstein AA, Drinkard BM, Diao G, Furst G, Dale JK, Straus SE, Gerber LH. Exploratory analysis of the relationships between aerobic capacity and self-reported fatigue in patients with rheumatoid arthritis, polymyositis, and chronic fatigue syndrome. PM R. 2009 Jul;1(7):620-8. PMID: 19627955

Patients with CFS have significantly decreased aerobic capacity. Self-reports of physical activity predicted VO(2peak), and may be used as an indicator of activity-based aerobic capacity. Self-reports of fatigue, however, did not correlate with VO(2peak) and hence are assessing something other than an index of aerobic capacity.


Thambirajah AA, Sleigh K, Stiver HG, Chow AW. Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls. Clin Invest Med. 2008 Dec 1;31(6):E319-27. PMID: 19032901

Heat shock protein expression following exercise is abnormal in CFS, suggesting an abnormal response to oxidative stress.  This has potential of serving as a biomarker.


Patrick Neary J, Roberts AD, Leavins N, Harrison MF, Croll JC, Sexsmith JR. Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome. Clin Physiol Funct Imaging. 2008 Nov;28(6):364-72. PMID: 18671793

Decreased cerebral oxygenation and blood flow may make contribute to the reduced exercise abilities in CFS.


Nijs J, Almond F, De Becker P, Truijen S, Paul L. Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial. Clin Rehabil. 2008 May;22(5):426-35. PMID: 18441039

Limiting both the intensity and duration of exercise prevents important health status changes following a walking exercise in people with CFS, but was unable to prevent short-term symptom increases.


Nijs J, Zwinnen K, Meeusen R, de Geus B, De Meirleir K. Comparison of two exercise testing protocols in patients with chronic fatigue syndrome. J Rehabil Res Dev. 2007;44(4):553-9. PMID: 18247252

CFS patients engaging in a stepwise exercise protocol had lower mechanical efficiency (ratio peak workload/peak oxygen uptake) than those engaging in a linear exercise protocol.


Nijs J, Demol S, Wallman K. Can submaximal exercise variables predict peak exercise performance in women with chronic fatigue syndrome? Arch Med Res. 2007 Apr;38(3):350-3. PMID: 17350488

This study aimed at examining whether physiological exercise variables at the submaximal level, defined as 75% of the age-predicted target heart rate, are able to predict peak exercise performance in women with chronic fatigue syndrome (CFS).


Yoshiuchi K, Cook DB, Ohashi K, Kumano H, Kuboki T, Yamamoto Y, Natelson BH. A real-time assessment of the effect of exercise in chronic fatigue syndrome. Physiol Behav. 2007 Dec 5;92(5):963-8. PMID: 17655887

CFS patients experienced increased physical symptoms after exercise, on average with a five-day delay. Psychological symptoms and cognitive functioning did not change after exercise.


Nijs J, Meeus M, De Meirleir K. Chronic musculoskeletal pain in chronic fatigue syndrome: recent developments and therapeutic implications. Man Ther. 2006 Aug;11(3):187-91. PMID: 16781183

CFS sufferers respond to incremental exercise with a lengthened and accentuated oxidative stress response, explaining muscle pain, postexertional malaise, and the decrease in pain threshold following graded exercise in CFS patients.


Cook DB, Nagelkirk PR, Poluri A, Mores J, Natelson BH. The influence of aerobic fitness and fibromyalgia on cardiorespiratory and perceptual responses to exercise in patients with chronic fatigue syndrome. Arthritis Rheum. 2006 Oct;54(10):3351-62. PMID: 17009309

In the overall sample, there were no significant differences in cardiorespiratory parameters between the CFS only group and the controls. However, the CFS plus FM group exhibited lower ventilation, lower end-tidal CO2, and higher ventilatory equivalent of carbon dioxide compared with controls, and slower increases in heart rate compared with both patients with CFS only and controls. Peak oxygen consumption, ventilation, and workload were lower in the CFS plus FM group. Subjects in both the CFS only group and the CFS plus FM group rated exercise as more effortful than did controls.


Nijs J, Meeus M, McGregor NR, Meeusen R, de Schutter G, van Hoof E, de Meirleir K. Chronic fatigue syndrome: exercise performance related to immune dysfunction. Med Sci Sports Exerc. 2005 Oct;37(10):1647-54. PMID: 16260962

There appears to be an association between intracellular immune deregulation and exercise performance in patients with CFS.


Jammes Y, Steinberg JG, Mambrini O, Brégeon F, Delliaux S. Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. J Intern Med. 2005 Mar;257(3):299-310. PMID: 15715687

Following exercise, CFS patients have lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability.


Nijs J, De Meirleir K. Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome. In Vivo. 2005 Nov-Dec;19(6):1013-21. PMID: 16277015

The 2′-5′ oligoadenylate (2-5 A) synthetase/RNase L pathway in CFS patients appears to be both upregulated and deregulated, and this seems to be related to performance during a graded exercise stress test.


Black CD, McCully KK. Time course of exercise induced alterations in daily activity in chronic fatigue syndrome. Dyn Med. 2005 Oct 28;4:10. PMID: 16255779

CFS patients who attempt to increase their activity by participating in a daily walking program have a difficult time maintaining that increase over time and usually compensate by reducing other activity.


Bazelmans E, Bleijenberg G, Voeten MJ, van der Meer JW, Folgering H. Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome. J Psychosom Res. 2005 Oct;59(4):201-8. PMID: 16223622

After exercise, CFS patients reported fatigue for an additional two days, compared to two hours for matched sedentary controls.


Snell CR, Vanness JM, Strayer DR, Stevens SR. Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS). In Vivo. 2005 Mar-Apr;19(2):387-90. PMID: 15796202

Abnormal immune activity related to oxidative stress, nitric oxide related toxicity and hyperactivation of Rnase-L is related to exercise intolerance in CFS patients.


Whistler T, Jones JF, Unger ER, Vernon SD. Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects. BMC Physiol. 2005 Mar 24;5(1):5. PMID: 15790422

Following an exercise challenge, CFS patients differed from controls on a variety of genes, including chromatin and nucleosome assembly, cytoplasmic vesicles, membrane transport and G protein-coupled receptor ontologies.  Differences in ion transport and ion channel activity were evident at baseline and exaggerated after exercise.


Nijs J, De Meirleir K. Prediction of peak oxygen uptake in patients fulfilling the 1994 CDC criteria for chronic fatigue syndrome. Clin Rehabil. 2004 Nov;18(7):785-92. PMID: 15573835

A technique to predict peak oxygen uptake in CFS patients was developed.


Whiteside A, Hansen S, Chaudhuri A. Exercise lowers pain threshold in chronic fatigue syndrome. Pain. 2004 Jun;109(3):497-9. PMID: 15157711

During exercise, normal people have higher pain thresholds and CFS patients have lower pain thresholds.


Nijs J, Vanherberghen K, Duquet W, De Meirleir K. Chronic fatigue syndrome: lack of association between pain-related fear of movement and exercise capacity and disability. Phys Ther. 2004 Aug;84(8):696-705. PMID: 15283620

This study shows a lack of correlation between kinesiophobia (fear of movement) and exercise capacity, activity limitations, or participation restrictions, at least in patients with CFS who are experiencing widespread muscle or joint pain.


Siemionow V, Fang Y, Calabrese L, Sahgal V, Yue GH. Altered central nervous system signal during motor performance in chronic fatigue syndrome. Clin Neurophysiol. 2004 Oct;115(10):2372-81. PMID: 15351380

CFS involves altered central nervous system signals in controlling voluntary muscle activities, especially when the activities induce fatigue.


McCully KK, Smith S, Rajaei S, Leigh JS Jr, Natelson BH. Muscle metabolism with blood flow restriction in chronic fatigue syndrome. J Appl Physiol. 2004 Mar;96(3):871-8. PMID: 14578362

CFS patients have evidence of hyperemic flow and reduced oxygen delivery, but this does not seem to result in disturbed muscle metabolism.


Nijs J, De Meirleir K, Wolfs S, Duquet W. Disability evaluation in chronic fatigue syndrome: associations between exercise capacity and activity limitations/participation restrictions. Clin Rehabil. 2004 Mar;18(2):139-48. PMID: 15053122

These results suggest a moderate association between exercise capacity and activity limitations/participation restrictions in patients with CFS. The observed correlations lack strength to predict activity limitations/ participation restriction based on exercise capacity parameters.


Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, Jones JF. Complement activation in a model of chronic fatigue syndrome. J Allergy Clin Immunol. 2003 Aug;112(2):397-403. PMID: 12897748

Exercise challenge induced significant increases of the complement split product C4a, but not C3a or C5a, at 6 hours after exercise only in the CFS group. This has potential of serving as a biomarker.


Vanness JM, Snell CR, Strayer DR, Dempsey L 4th, Stevens SR. Subclassifying chronic fatigue syndrome through exercise testing. Med Sci Sports Exerc. 2003 Jun;35(6):908-13. PMID: 12783037

Severely affected CFS patients are more impaired during exercise stress tests in terms of peak systolic blood pressure and peak heart rate.


Snell CR, Vanness JM, Strayer DR, Stevens SR. Physical performance and prediction of 2-5A synthetase/RNase L antiviral pathway activity in patients with chronic fatigue syndrome. In Vivo. 2002 Mar-Apr;16(2):107-9. PMID: 12073768

Seventy-three CFS patients performed a graded exercise test to voluntary exhaustion. Forty-six patients had elevated RNase L levels. The elevated RNase L group had a lower peak V02 and duration than the normal group, but a higher KPS. Both Rnase L and exercise intolerance have potential as biomarkers for CFS.


Ohashi K, Yamamoto Y, Natelson BH. Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome. Physiol Behav. 2002 Sep;77(1):39-44. PMID: 12213500

CFS patients had an abnormal lengthening (P < .05) of mean circadian period (MCP) after exercise that was longer than 24 hours.


Farquhar WB, Hunt BE, Taylor JA, Darling SE, Freeman R. Blood volume and its relation to peak O(2) consumption and physical activity in patients with chronic fatigue. Am J Physiol Heart Circ Physiol. 2002 Jan;282(1):H66-71. PMID: 11748048

CFS patients tend to have low blood volume and low peak oxygen consumption, and this seems to be related to their exercise intolerance.


Inbar O, Dlin R, Rotstein A, Whipp BJ. Physiological responses to incremental exercise in patients with chronic fatigue syndrome. Med Sci Sports Exerc. 2001 Sep;33(9):1463-70. PMID: 11528333

CFS patients demonstrated significantly lower cardiovascular as well as ventilatory values at peak exercise, compared with the control group.


Jason LA, Melrose H, Lerman A, Burroughs V, Lewis K, King CP, Frankenberry EL. Managing chronic fatigue syndrome: overview and case study. AAOHN J. 1999 Jan;47(1):17-21. PMID: 10205371

The basic principles of envelope theory are explained. By not overexerting themselves, people with CFS can avoid the setbacks and relapses that commonly occur in response to overexertion while increasing their tolerance to activity.


McCully KK, Natelson BH. Impaired oxygen delivery to muscle in chronic fatigue syndrome. Clin Sci (Lond). 1999 Nov;97(5):603-8; discussion 611-3. PMID: 10545311

Compared to healthy controls, CFS patients suffered abnormally reduced time constant of oxygen delivery and oxidative metabolism following exercise.


Mullis R, Campbell IT, Wearden AJ, Morriss RK, Pearson DJ. Prediction of peak oxygen uptake in chronic fatigue syndrome. Br J Sports Med. 1999 Oct;33(5):352-6. PMID: 10522640

Using a simple to administer maximal exercise test on a cycle ergometer, it is possible to predict accurately the VO2peak of a patient with CFS from peak work rate alone. This value can then be used as an aid to setting appropriate exercise intensity for a rehabilitation programme.


Paul L, Wood L, Behan WM, Maclaren WM. Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome. Eur J Neurol. 1999 Jan;6(1):63-9. PMID: 10209352

Throughout a period of exercise, patients were able to exercise less than controls. Recovery was prolonged in the patient group, however, with a significant difference compared to initial amount of exercise being evident during the recovery phase after exercise (P = 0.001) and also at 24 h (P < 0.001). These findings support the clinical complaint of delayed recovery after exercise in patients with CFS.


LaManca JJ, Sisto SA, DeLuca J, Johnson SK, Lange G, Pareja J, Cook S, Natelson BH. Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome. Am J Med. 1998 Sep 28;105(3A):59S-65S. PMID: 9790484

After a physically demanding exercise, CFS subjects demonstrated impaired cognitive processing compared with healthy individuals.


Blackwood SK, MacHale SM, Power MJ, Goodwin GM, Lawrie SM. Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression. J Neurol Neurosurg Psychiatry. 1998 Oct;65(4):541-6. PMID: 9771781

After exertion, patients with chronic fatigue syndrome showed a greater decrease than healthy controls on everyday tests of focused and sustained attention, as well as greater deterioration than depressed patients on the focused attention task.


Lane RJ, Barrett MC, Woodrow D, Moss J, Fletcher R, Archard LC. Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 1998 Mar;64(3):362-7. PMID: 9527150

Muscle histometry in patients with chronic fatigue syndrome generally did not show the changes expected as a result of inactivity. However, patients with abnormal lactate responses to exercise had a significantly lower proportion of mitochondria rich type 1 muscle fibres.


Fischler B, Dendale P, Michiels V, Cluydts R, Kaufman L, De Meirleir K. Physical fatigability and exercise capacity in chronic fatigue syndrome: association with disability, somatization and psychopathology. J Psychosom Res. 1997 Apr;42(4):369-78. PMID: 9160276

The authors present evidence against an association in CFS between avoidance of physically demanding tasks and early anaerobic metabolism during effort.


Kent-Braun JA, Sharma KR, Weiner MW, Massie B, Miller RG. Central basis of muscle fatigue in chronic fatigue syndrome. Neurology. 1993 Jan;43(1):125-31.

Voluntary activation of the tibialis was significantly lower in CFS patients during maximal sustained exercise.


Wong R, Lopaschuk G, Zhu G, Walker D, Catellier D, Burton D, Teo K, Collins-Nakai R, Montague T. Skeletal muscle metabolism in the chronic fatigue syndrome. In vivo assessment by 31P nuclear magnetic resonance spectroscopy. Chest. 1992 Dec;102(6):1716-22. PMID: 1446478

CFS patients reach exhaustion much more rapidly than normal subjects, at which point they also have relatively reduced intracellular concentrations of ATP. These data suggest a defect of oxidative metabolism with a resultant acceleration of glycolysis in the working skeletal muscles of CFS patients.


Montague TJ, Marrie TJ, Klassen GA, Bewick DJ, Horacek BM. Cardiac function at rest and with exercise in the chronic fatigue syndrome. Chest. 1989 Apr;95(4):779-84. PMID: 2924607

Patients with chronic fatigue syndrome have normal resting cardiac function but a markedly abbreviated exercise capacity characterized by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved.



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