Muscles and PEM Studies

“Bioenergetic muscle dysfunction is evident in CFS/ME, with a tendency towards an overutilisation of the lactate dehydrogenase pathway...mitochondrial dysfunction plays a key role in CFS/ME aetiology. Lowered ATP production, impaired oxidative phosphorylation, and mitochondrial damage have been reported in patients with CFS/ME. ”

— Rutherford et al., Journal of Aging Research

Quick Summary

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Extended List of Studies (by year)

2015 - 2019

Peak Oxygen Uptake in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Meta-Analysis.
Franklin JD, Atkinson G, Atkinson JM, Batterham AM. Int J Sports Med. 2019
Synthesis of the available evidence indicates that CFS/ME patients have a substantially reduced VO2peak compared to controls. (“Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is an illness where patients have biological defects in aerobic metabolism. How do we know? 32 independent scientific studies have shown people with ME have significantly reduced VO2peak.”- Mark Guthridge)

Deconstructing post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome: A patient-centered, cross-sectional survey. [PDF]
Chu L, Valencia IJ, Garvert DW, Montoya JG. PloS One. 2018
Fatigue was the most commonly exacerbated symptom but cognitive difficulties, sleep disturbances, headaches, muscle pain, and flu-like feelings were cited by over 30% of subjects. Sixty percent of subjects experienced at least one inflammatory/ immune-related symptom. Subjects also cited gastrointestinal, orthostatic, mood-related, neurologic and other symptoms.

Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study. [Full Text] [PDF]
Hodges LD, Nielsen T, Baken D. Clin Physiol Funct Imaging. 2018

The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome. [PDF]
Jason LA, Holtzman CS, Sunnquist M, Cotler J. J Health Psychol. 2018

Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. [Full Text] [PDF]
Moneghetti KJ, Skhiri M, Contrepois K, Kobayashi Y, Maecker H, Davis M, Snyder M, Haddad F, Montoya JG.
Sci Rep. 2018

Old muscle in young body: an aphorism describing the Chronic Fatigue Syndrome. [PDF]
Pietrangelo T, Fulle S, Coscia F, Gigliotti PV, Fanò-Illic G. Eur J Transl Myol. 2018
In particular, 1. presence of oxidative damage of lipid component of biological membranes and DNA not compensated by the increase of the scavenger activity; 2. Excitation-Contraction (E-C) alteration with modification of Ca2+ transport; 3. passage from slow to fast fiber phenotype; 4. inability to increase glucose uptake; 5. presence of mitochondrial dysfunction; and 6. genes expressed differentially (particularly those involved in energy production). The skeletal muscles of CFS / ME patients show a significant alteration of the oxidative balance due to mitochondrial alteration and of the fiber phenotype composition as shown in sarcopenic muscles of the elderly.

The data support the hypothesis that patients with CFS are subjected to some of the problems typical for muscle aging, which is probably related to disorders of muscle protein synthesis and biogenesis of mitochondria.

Exercise-induced hyperalgesia, complement system and elastase activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - a secondary analysis of experimental comparative studies.
[Full Text] [PDF]
Polli A, Van Oosterwijck J, Meeus M, Lambrecht L, Nijs J, Ickmans K. Scand J Pain. 2018

[HIGHLIGHT] Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. [PDF]
Stevens, S. et al., Frontiers in Pediatrics. 2018
In this patient population, CPET also elicits a robust post-exertional symptom flare (termed, post-exertional malaise); a cardinal symptom of the disease. CPET measures are highly reliable and reproducible in both healthy and diseased populations. However, evidence to date indicates that ME/CFS patients are uniquely unable to reproduce CPET measures during a second test, despite giving maximal effort during both tests, due to the effects of PEM on energy production.

Exercise – induced changes in cerebrospinal uid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control. [PDF]
Baraniuk JN, Shivapurkar N. Scientific Reports. 2017

Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: case-control study.
Clark LV, et al. Clin Exp Immunol. 2017

[HIGHLIGHT] Mechanisms Explaining Muscle Fatigue and Muscle Pain in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a Review of Recent Findings. [Full Text]
Gerwyn M, Maes M. Curr Rheumatol Rep. 2017
Here, we review potential causes of muscle dysfunction seen in many patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) such as the effects of oxidative and nitrosative stress (O&NS) and mitochondrial impairments together with reduced heat shock protein production and a range of metabolic abnormalities.

Several studies published in the last few years have highlighted the existence of chronic O&NS, inflammation, impaired mitochondrial function and reduced heat shock protein production in many patients with ME/CFS. These studies have also highlighted the detrimental effects of chronically elevated O&NS on muscle functions such as reducing the time to muscle fatigue during exercise and impairing muscle contractility. Mechanisms have also been revealed by which chronic O&NS and or impaired heat shock production may impair muscle repair following exercise and indeed the adaptive responses in the striated muscle to acute and chronic increases in physical activity. The presence of chronic O&NS, low-grade inflammation and impaired heat shock protein production may well explain the objective findings of increased muscle fatigue, impaired contractility and multiple dimensions of exercise intolerance in many patients with ME/CFS.

Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study.
Hodges LD, et al. Clin Physiol Funct Imaging. 2017

[HIGHLIGHT] Understanding Muscle Dysfunction in Chronic Fatigue Syndrome. [Full Text] [PDF]
*Rutherford G, Manning P, Newton JL. J Aging Res. 2016
Bioenergetic muscle dysfunction is evident in CFS/ME, with a tendency towards an overutilisation of the lactate dehydrogenase pathway following low-level exercise, in addition to slowed acid clearance after exercise.
There is evidence to suggest that mitochondrial dysfunction plays a key role in CFS/ME aetiology. Lowered ATP production, impaired oxidative phosphorylation, and mitochondrial damage have been reported in patients with CFS/ME [23, 24]. Moreover, CFS/ME patients share common skeletal muscle symptoms associated with diseases linked to mitochondrial dysfunction, for example, muscle pain, fatigue, and cramping [61, 62].

There is accumulating evidence to suggest that abnormally high lactate levels and intracellular acidosis exhibited in patients with CFS/ME are the result of impaired mitochondrial function [61, 63]. For example, CFS/ME patients exhibit profound and sustained intracellular acidosis of the peripheral musculature following relatively low-level exercise. This results in a decreased anaerobic threshold (AT) due to an overutilisation of the lactate dehydrogenase pathway [15, 41]. Upon the point of exhaustion CFS/ME patients have been reported to exhibit intracellular ATP concentrations that are lower than those found in nondiseased control participants, which could be indicative of dysfunction in oxidative metabolism. Moreover, in a recent review [61] the authors concluded the response to exercise exhibited by CFS/ME patients to be typical of that reported in individuals with mitochondrial disease. Additionally, there were also a number of similarities between symptoms of mitochondrial disease and the physiosomatic symptoms of CFS/ME. For example, muscle pain, cramps, weakness, and myalgia's [54, 62, 64].

Mitochondrial dysfunction in CFS/ME may be explained by not only elevated oxidative and nitrosative stress but also increased immune-inflammatory stress pathways [65]. Interestingly, chronic low-grade inflammation in CFS/ME has been demonstrated through increased levels of proinflammatory cytokines (IL-1, TNF-α) and a movement towards a Th2 dependent immune response, in addition to inflammatory mediators including NF-κB and elastase [64].

Evidence for sensitized fatigue pathways in patients with chronic fatigue syndrome. [PDF]
Staud R, Mokthech M, Price DD, Robinson ME. Pain. 2016
Our findings provide indirect evidence for significant contributions of peripheral tissues to the increased exercise-related fatigue in CFS patients consistent with sensitization of fatigue pathways.

Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with chronic fatigue syndrome. [PDF]
Brown AE, Jones DE, Walker M, Newton JL. PLoS One. 2015
The authors found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMP kinase, impaired stimulation of glucose uptake and diminished release of IL6.

In silico analysis of exercise intolerance in myalgic encephalomyelitis/ chronic fatigue syndrome. [Full Text]
Lengert N, Drossel B. Biophys Chem. 2015
The authors present a model which simulates metabolite dynamics in skeletal muscles during exercise and recovery. CFS simulations exhibit critically low levels of ATP, where an increased rate of cell death would be expected. To stabilize the energy supply at low ATP concentrations the total adenine nucleotide pool is reduced substantially causing a prolonged recovery time even without consideration of other factors, such as immunological dysregulations and oxidative stress. Repeated exercises worsen this situation considerably. Furthermore, CFS simulations exhibited an increased acidosis and lactate accumulation consistent with experimental observations.

Submaximal exercise testing with near-infrared spectroscopy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients compared to healthy controls: a case–control study. [PDF]
Miller RR, Reid WD, Mattman A, Yamabayashi C, Steiner T, Parker S, Gardy J, Tang P, Patrick DM. Journal of Translational Medicine. 2015

Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial. [PDF]
Sharpe M, Goldsmith KA, Johnson AL, Chalder T, Walker J, White PD. The Lancet Psychiatry. 2015

Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). [Full Text] [PDF]
Shukla SK, Cook D, Meyer J, Vernon SD, Le T, Clevidence D, Robertson CE, Schrodi SJ, Yale S, Frank DN.
PloS One. 2015
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.

The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Vink M. Journal of Neurology and Neurobiology. 2015
This study found that in severe ME, both the oxidative phosphorylation and the lactic acid excretion are impaired, and the combination of these two is responsible for the main characteristic of ME, the abnormally delayed muscle recovery after doing trivial things. The muscle recovery is further delayed by immune changes, including intracellular immune dysfunctions, and by lengthened and accentuated oxidative stress, but also by exercise metabolites, which work on the sensitive receptors in the dorsal root ganglions, which in severe ME are chronically inflamed, and are therefore much more sensitive to these metabolites, which are produced in high quantities in response to trivial exercise, which for ME patients, due to the underlining metabolic problem, is strenuous exercise. And a similar problem is most likely responsible for the abnormally delayed brain recovery after doing trivial things.

This study also shows that the two metabolic problems are the result of an impaired oxygen uptake into the muscle cells or their mitochondria and in combination with the Norwegian Rituximab studies, which suggest that ME is an autoimmune disease, it is suggestive that antibodies are directly or indirectly blocking the oxygen uptake into the muscle cells or their mitochondria.

2010-2014

[HIGHLIGHT] Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment. [Full Text] [PDF]
Keller BA, Pryor JL, Giloteaux L. J Transl Med. 2014
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. Our work confirms that repeated CPETs warrant consideration as a clinical indicator for diagnosing ME/CFS. Furthermore, if based on only one CPET, functional impairment classification will be mis-identified in many ME/CFS participants.

Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review. [PDF]
Nijs J, Nees A, Paul L, De Kooning M, Ickmans K, Meeus M, Van Oosterwijck J. Exerc Immunol Rev. 2014
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.

Impaired range of motion of limbs and spine in chronic fatigue syndrome.
Rowe PC, Marden CL, Flaherty MA, Jasion SE, Cranston EM, Johns AS, Fan J, Fontaine KR, Violand RL.
J Pediatr. 2014
Impaired range of motion is more common in subjects with CFS than in healthy adolescents and young adults matched by sex and joint hypermobility. Adding a longitudinal strain to the nerves and soft tissues provoked symptoms in some subjects with CFS.

Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome.
[Full Text] [PDF]
Vermeulen RC, Vermeulen van Eck IW. J Transl Med. 2014
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.

Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome. [PDF]
Snell CR, Stevens SR, Davenport TE, Van Ness JM. Physical Therapy. 2013

Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome. [Full Text]
Strahler J, Fischer S, Nater UM, Ehlert U, Gaab J. Biol Psychol. 2013
The researchers found evidence of altered sympathetic-neural and sympathetic adrenomedulla reactivity in CFS. Exercise stress revealed a subtle catecholaminergic hyporeactivity in CFS patients.

Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case–control study.
[PDF]
Jones DEJ, Hollingsworth KG, Jakovljevic D, Fattakhova G, Pairman J, Blamire, AM, Trenell MI, Newton JL. European Journal of Clinical Investigation. 2012

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. [PDF]
White AT, Light AR, Hughen RW, Vanhaitsma TA, Light KC. Psychosom Med. 2012
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.

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

**Also see ME Research article, bookmarked

Serotonergic descending inhibition in chronic pain: design, preliminary results and early cessation of a randomized controlled trial. [Full Text] [PDF]
Meeus M, Ickmans K, De Clerck LS, Moorkens G, Hans G, Grosemans S, Nijs J.In Vivo. 2011
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.

Symptom fluctuations and daily physical activity in patients with chronic fatigue syndrome: a case-control study. [Full Text] [PDF]
Meeus M, van Eupen I, van Baarle E, De Boeck V, Luyckx A, Kos D, Nijs J. Arch Phys Med Rehabil. 2011
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.

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

Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. [PDF]
White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al. The Lancet. 2011

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

Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome. [PDF]
Jones DEJ, Hollingsworth KG, Taylor R, Blamire AM, Newton JL. J Intern Med. 2010
In this study, we have demonstrated that patients with CFS/ME have substantial abnormalities in the recovery of intramuscular pH following a standardised level of exercise. Proton efflux from muscle (critical for acidosis resolution) is substantially lower immediately postexercise: in normal controls, it is well established that this is the point of maximal proton efflux. In CFS/ME patients, this immediate fast removal of protons from the muscle does not occur. The time for proton efflux to reach a maximum is significantly prolonged compared to control subjects: the peak rate of proton efflux is also substantially impaired in CFS/ME patients. There is a close relationship between the degree of acidosis and proton efflux suggesting a closely regulated process: this has been observed in controls in other studies, and the pH changes observed in the control group are also in agreement with similar studies. In CFS/ME patients this relationship is lost. In addition, autonomic dysfunction assessed in the current study by total heart rate variability, is associated with dysregulation of pH recovery. There are two ways in which autonomic dysfunction could lead to abnormalities of muscle function. Studies have suggested that the autonomic nervous system (particularly the sympathetic branch) plays an important role in the drive of transporters in muscle that remove acid, in particular, the sodium/proton anti‐porter. A further mechanism that requires evaluation is the effect that the autonomic nervous system has upon the calibre of vessels ‘draining’ blood from the muscle it is possible that this may also have an impact upon the muscles ability to remove acid down stream.

Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. [PDF]
Maes M, Twisk FN. BMC Med. 2010
The authors describe how physiological abnormalities related to inflammatory, immune, oxidative and nitrosative pathways interfere with exercise tolerance in CFS.

Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta. [Full Text] [PDF]
Nijs J, Van Oosterwijck J, Meeus M, Lambrecht L, Metzger K, Frémont M, Paul L. J Intern Med. 2010

Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study.
[Full Text]
Suárez A, Guillamo E, Roig T, Blázquez A, Alegre J, Bermúdez J, Ventura JL, García-Quintana AM, Comella A, Segura R, Javierre C. J Womens Health (Larchmt). 2010
CFS patients had a higher increase in nitric oxide metabolites after exercise than did controls.

Postexertional malaise in women with chronic fatigue syndrome. [Full Text]
VanNess JM, Stevens SR, Bateman L, Stiles TL, Snell CR. J Womens Health (Larchmt). 2010
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.

Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an experimental study. [PDF]
Van Oosterwijck J, Nijs J, Meeus M, Lefever I, Huybrechts L, Lambrecht L, Paul L. J Intern Med. 2010
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.

Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. [Full Text] [PDF]
Vermeulen RC, Kurk RM, Visser FC, Sluiter W, Scholte HR. J Transl Med. 2010
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.

Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial. [PDF]
Wearden AJ, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK, Peters S. BMJ. 2010

Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome.
[Full Text] [PDF]
White AT, Light AR, Hughen RW, Bateman L, Martins TB, Hill HR, Light KC. Psychophysiology. 2010
CFS patients often display negative responses to exercise, as a result of abnormal inflammatory cytokine activity. Increased cytokine activity, decreased intramuscular pH, autonomic dysfunction lower gross and net oxygen uptake. Following exercise, CFS patients have lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability.

2005-2009

Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses.
Jammes Y, et al. J Intern Med. 2009.

The impact of energy modulation on physical functioning and fatigue severity among patients with ME/CFS.
[PDF]
Jason L, Benton M, Torres-Harding S, Muldowney K. Patient Educ Couns. 2009
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.

[HIGHLIGHT] Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects. [Full Text] [PDF]
Light AR, White AT, Hughen RW, Light KC. J Pain. 2009
Muscle fatigue and pain are major symptoms of CFS. After moderate exercise, CFS and CFS-FMS patients show enhanced gene expression for receptors detecting muscle metabolites and for SNS (Sympathetic Nervous System) and IS (Immune System), which correlate with these symptoms.

Chronic fatigue syndrome: la bête noire of the Belgian health care system.
Maes M, Twisk FN. Neuro Endocrinol Lett. 2009
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.

Physiological cost of walking in those with chronic fatigue syndrome (CFS): a case-control study.
Paul L, Rafferty D, Marshal R. Disabil Rehabil. 2009
Compared to controls walking at the same speed, CFS patients had a lower gross and net oxygen uptake and suffered a higher physiological cost.

Functional characterization of muscle fibres from patients with chronic fatigue syndrome: case-control study.
[Full Text] [PDF]
Pietrangelo T, Toniolo L, Paoli A, Fulle S, Puglielli C, Fanò G, Reggiani C. Int J Immunopathol Pharmacol. 2009
This study supports the view that muscle tissue is directly involved in the pathogenesis of CSF and it might contribute to the early onset of fatigue typical of the skeletal muscles of CFS patients.

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. [Full Text]
Twisk FN, Maes M. Neuro Endocrinol Lett. 2009
The authors discuss how the use of exercise therapy in CFS may be harmful to patients.

Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome. [PDF]
Neary PJ, Roberts AD, Leavins N, Harrison MF, Croll JC, Sexsmith JR. Clin Physiol Funct Imaging. 2008
Decreased cerebral oxygenation and blood flow may make contribute to the reduced exercise abilities in CFS.

Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls.
Thambirajah AA, Sleigh K, Stiver HG, Chow AW. Clin Invest Med. 2008
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.

Chronic musculoskeletal pain in patients with the chronic fatigue syndrome: a systematic review.
Meeus M, Nijs J, Meirleir KD. Eur J Pain. 2007
Chronic pain is important in CFS and needs to be studied more.

Chronic musculoskeletal pain in chronic fatigue syndrome: recent developments and therapeutic implications.
[Full Text]
Nijs J, Meeus M, De Meirleir K. Man Ther. 2006
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.

Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. [Full Text] [PDF]
Jammes Y, Steinberg JG, Mambrini O, Brégeon F, Delliaux S. J Intern Med. 2005
Following exercise, CFS patients have lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability.

Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS). [PDF]
Snell CR, Vanness JM, Strayer DR, Stevens SR. In Vivo. 2005
Abnormal immune activity related to oxidative stress, nitric oxide related toxicity and hyperactivation of Rnase-L is related to exercise intolerance in CFS patients.

2000-2004

Altered central nervous system signal during motor performance in chronic fatigue syndrome. [Full Text]
Siemionow V, Fang Y, Calabrese L, Sahgal V, Yue GH. Clin Neurophysiol. 2004
CFS involves altered central nervous system signals in controlling voluntary muscle activities, especially when the activities induce fatigue.

Blood volume and its relation to peak O(2) consumption and physical activity in patients with chronic fatigue.
[Full Text] [PDF]
Farquhar WB, Hunt BE, Taylor JA, Darling SE, Freeman R. Am J Physiol Heart Circ Physiol. 2002
CFS patients tend to have low blood volume and low peak oxygen consumption, and this seems to be related to their exercise intolerance.

Pre-2000

Managing chronic fatigue syndrome: overview and case study.
Jason LA, Melrose H, Lerman A, Burroughs V, Lewis K, King CP, Frankenberry EL. AAOHN J. 1999
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.

Impaired oxygen delivery to muscle in chronic fatigue syndrome. [Full Text]
McCully KK, Natelson BH. Clin Sci (Lond). 1999
Compared to healthy controls, CFS patients suffered abnormally reduced time constant of oxygen delivery and oxidative metabolism following exercise.

Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome.
Paul L, Wood L, Behan WM, Maclaren WM. Eur J Neurol. 1999
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.

Psychology: Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression.
[PDF]
Blackwood SK, MacHale SM, Power MJ, Goodwin GM, Lawrie SM. J Neurol Neurosurg Psychiatry. 1998
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.

Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome. [Full Text]
LaManca JJ, Sisto SA, DeLuca J, Johnson SK, Lange G, Pareja J, Cook S, Natelson BH. Am J Med. 1998
After a physically demanding exercise, CFS subjects demonstrated impaired cognitive processing compared with healthy individuals.

Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome. [Full Text] [PDF]
Lane RJ, Barrett MC, Woodrow D, Moss J, Fletcher R, Archard LC. J Neurol Neurosurg Psychiatry. 1998

Alteration of spatial-temporal parameters of gait in Chronic Fatigue Syndrome patients. [Full Text] [PDF]
Saggini R, Pizzigallo E, Vecchiet J, Macellari V, Giacomozzi C. J Neurol Sci. 1998
The gait of CFS patients revealed significant abnormalities in the symmetry indices of the bilateral parameters and in the linear relationships among parameters, and between these parameters and the physical characteristics of the patients. The abnormalities were present as from the beginning of the gait, which indicates that they are unlikely to be caused by the rapid increasing fatigue. This strengthens the hypothesis of a direct involvement of the central nervous system (CNS) in the onset of the disease.

Reduced oxidative muscle metabolism in chronic fatigue syndrome.
McCully KK, Natelson BH, Iotti S, Sisto S, Leigh JS Jr. Muscle Nerve. 1996
Oxidative metabolism is reduced in CFS patients compared to sedentary controls.

Gait abnormalities in chronic fatigue syndrome. [PDF]
Boda WL, Natelson BH, Sisto SA, Tapp WN. J Neurol Sci. 1995
The researchers evaluated their clinical impression that patients with CFS did not walk normally, finding that they did indeed have objective gait abnormalities.

Acylcarnitine deficiency in chronic fatigue syndrome.
Kuratsune H, Yamaguti K, Takahashi M, Misaki H, Tagawa S, Kitani T. Clin Infect Dis. 1994
One of the characteristic complaints of patients with chronic fatigue syndrome (CFS) is the skeletal muscle-related symptom. However, the abnormalities in the skeletal muscle that explain the symptom are not clear. Herein, we show that our patients with CFS had a deficiency of serum acylcarnitine. As carnitine has an important role in energy production and modulation of the intramitochondrial coenzyme A (CoA)/acyl-CoA ratio in the skeletal muscle, this deficiency might induce an energy deficit and/or abnormality of the intramitochondrial condition in the skeletal muscle, thus resulting in general fatigue, myalgia, muscle weakness, and postexertional malaise in patients with CFS. Furthermore, the concentration of serum acylcarnitine in patients with CFS tended to increase to the normal level with the recovery of general fatigue. Therefore, the measurement of acylcarnitine would be a useful tool for the diagnosis and assessment of the degree of clinical manifestation in patients with CFS.

Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. [PDF]
Peterson PK, Sirr SA, Grammith FC, Schenck CH, Pheley AM, Hu S, Chao CC. Clin Diagn Lab Immunol. 1994

Chronic fatigue: electromyographic and neuropathological evaluation.
Connolly S, Smith DG, Doyle D, Fowler CJ. J Neurol. 1993
Muscle fibre density estimation may be a useful way of identifying a subgroup of CFS sufferers with a possible primary muscle disorder.

Central basis of muscle fatigue in chronic fatigue syndrome.
Kent-Braun JA, Sharma KR, Weiner MW, Massie B, Miller RG. Neurology. 1993
Voluntary activation of the tibialis was significantly lower in CFS patients during maximal sustained exercise.

Biochemical and muscle studies in patients with acute onset post-viral fatigue syndrome.
Preedy VR, Smith DG, Salisbury JR, Peters TJ. J Clin Pathol. 1993
Patients with acute onset post viral fatigue syndrome lose muscle protein synthetic potential, but not muscle bulk.

Skeletal muscle metabolism in the chronic fatigue syndrome. In vivo assessment by 31P nuclear magnetic resonance spectroscopy. [Full Text] [PDF]
Wong R, Lopaschuk G, Zhu G, Walker D, Catellier D, Burton D, Teo K, Collins-Nakai R, Montague T. Chest. 1992
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.

Mitochondrial abnormalities in the postviral fatigue syndrome.
Behan WM, More IA, Behan PO. Acta Neuropathol. 1991
Muscle biopsies of patients with postviral fatigue syndrome showed mild to severe atrophy of type II fibres in 39 biopsies, with a mild to moderate excess of lipid. On ultrastructural examination, 35 of these specimens showed branching and fusion of mitochondrial cristae. Mitochondrial degeneration was obvious in 40 of the biopsies with swelling, vacuolation, myelin figures and secondary lysosomes.

Cardiac function at rest and with exercise in the chronic fatigue syndrome.
Montague TJ, Marrie TJ, Klassen GA, Bewick DJ, Horacek BM. Chest. 1989
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.

Postviral fatigue syndrome: persistence of enterovirus RNA in muscle and elevated creatine kinase.
[Full Text] [PDF]
Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. J R Soc Med. 1988