Energy failure in ME/CFS

This is an English translation of the Norwegian blogpost “ME-syke har energisvikt.”

ME/CFS is an illness it’s hard to understand. And in the absence of a diagnostic test, the opinions are many and strong about both the illness and who suffer from it. But did you know that a 2-day bicycle test can identify the patients with defective energy metabolism?

In this blogpost, Jørn Tore Haugen has summarized 24 studies showing abnormal lactate and oxygen values ​​in CFS/ME-patients following such a bicycle test (CPET). He has also made an overview of lectures and webinars for those who want to learn more.

But first a short lesson about mitochondria – the cells’ energy powerhouse, and PEM – the hallmark symptom of ME/CFS.


The body’s petrol is called ATP. It’s made inside the cells by the help of mitochondria – which are found in all the cells except for the red blood cells. “The mitochondria are the body’s energy factories. When they fail, we can get seriously ill.” (Quote article in Aftenposten, 2017)

When the mitochondria fail, or processes in the mitochondria are inhibited, the energy production is impaired – and the cells make more lactic acid (lactate). At least seven research groups believe to link ME patients’ lack of energy to something in their blood. Several studies show that blood serum from ME patients changes the cells to healthy controls, while the patients’ cells are repaired when exposed to serum from healthy controls. Please read more in the blogpost: “CFS/ME – A “factor” in plasma?

Researchers in New Zealand recently published two new studies, where one shows dysfunction in the mitochondria and the other one found changes in five DNA codes. Both studies support that ME/CFS is a biological illness.

“They are definitely organic rather than psychological changes and are indicative of a complex disease involving many physiological systems of the body.

Our studies have shown unequivocally this is not a psychosomatic illness.”

Research supports involvement of both the central, peripheral and autonomic nervous system, the immune system and energy metabolism in ME/CFS.

Learn more from U.S ME/CFS Clinician Coalition.

Cred pic: MEAction

What is PEM?

PEM is the abbreviation for Post Exertional Malaise. “The illness within the illness” is a good explanation by Prof. Anthony Komaroff.

Some people think PEM is the same as being deconditioned or having sore muscles after exercise. That’s wrong. The Norwegian researchers behind the planned study on Lightning Process believe PEM is due to negative thoughts and feelings, and will let a Psychologist take care of patients who get worse. That’s also very wrong.

PEM is a physical and mental/cognitive deterioration after all kinds of activity, and which exceeds the individual’s tolerance limit – including positive and happy activities such as being social, attending a course or reading a book. Another word is activity intolerance.

PEM is the defining feature of ME/CFS, and a required symptom according to the IOM-report and strict diagnostic criteria:

From Prof. Betsy Keller’s presentation about PEM and 2-day CPET
at the Swedish ME/CFS conference 2020

The US National Institutes of Health (NIH) recently published a study on PEM, in which they mapped triggers, symptoms, duration and consequences.

The study shows a wide range of symptoms, which can be divided into three core categories; exhaustion, cognitive difficulties and neuromuscular complaints. There were few differences between daily PEM and following CPET, but slightly more in onset, peak and recovery.

PEM can start immediately or gradually, and last anywhere from a few hours to several months and years. According to the patients the best way to recover is to lie flat with no sensory input.

“It was quite striking to hear the extent to which PEM can affect their quality of life. The widespread body symptoms, the unpredictability of PEM, and the sometimes-lengthy recovery greatly hindered individuals’ ability to live a ‘normal’ life. ” Quote Barbara Stussmann, Lead author.

Copies from the researchers’ presentation at Solve CFS/ME’s Webinar, December 2020:

Patients experiences

What is a CPET?

Cardiopulmonary Exercise Test (CPET) is a bicycle test which measures the heart, lungs and muscles’ ability to deliver and use oxygen to make energy.

Several studies show that ME patients are unable to recreate their own test results following CPET, and have abnormal oxygen uptake and increased lactate production on the second day. This indicates dysfunction in the energy metabolism, which may explain and prove the patients’ lack of energy as well as PEM.

A 2-day CPET can work as a biomarker for ME/CFS, but is also potentially harmful to the patients.

The Norwegian MD Katarina Lien published a 2-day CPET study in 2019, and in an interview with NRK EKKO (radio) she said that “ME-patients are intolerante to exercise.”

From Prof. Betsy Keller’s presentation at the Swedish ME conference 2020

Overview studies

The overview has been prepared by Jørn Tore Haugen. For an overview incl. study references, please see here.

  1. The Prospects of the Two-Day Cardiopulmonary Exercise Test (CPET) in ME/CFS Patients: A Meta-Analysis (2020)

    Conclusion: «The meta-analysis indicates a significant alteration of workload at VT especially on the 2nd day of CPET in ME/CFS patients. Accordingly, the two-day CPET could be considered as one of the potential objective assessment tools for PEM in ME/CFS patients.»
  2. Post-exertional symptoms distinguish Myalgic Encephalomyelitis/Chronic Fatigue Syndrome subjects from healthy controls (2020)

    Conclusion: «A standardized exertional stimulus produced prolonged, diverse symptoms in ME/CFS subjects. This provides clues to the underlying pathophysiology of ME/CFS, leading to improved diagnosis and treatment.»
  3. Validity of 2-Day Cardiopulmonary Exercise Testing in Male Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome  (2020)

    Conclusion: «The larger sample size of this study improves the confidence with which we can conclude that, like females, males have a similar decrement on day 2 of the consecutive day exercise tests. Our results confirm that 2-day CPET can be used in males to demonstrate the decrease in exercise capacity in research studies and if needed for social security claims. Further comparisons are needed to explore whether the absolute or relative changes in VO2 and workload on day 2 versus day 1 are similar across a wider range of clinical severity, and whether these values differ for subgroups with specific comorbid conditions.»
  4. Two-Day Cardiopulmonary Exercise Testing in Females with a Severe Grade of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison with Patients with Mild and Moderate Disease (2020)

    Conclusion: «This is the first study to demonstrate that disease severity negatively influences exercise capacity in female ME/CFS patients. Finally, this study shows that the deterioration in peak workload from day-1 to day-2 is largest in the severe ME/CFS patient group.»
  5. Properties of measurements obtained during cardiopulmonary exercise testing in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (2020)

    Conclusion: «CPET measurements demonstrated moderate to high reliability for individuals with ME/CFS. Comparing subjects with ME/CFS and control subjects yielded moderate to large effect sizes on all CPET measurements. MDC95 for all individuals with ME/CFS generally exceeded control subjects and CoVs for CPET measurements were comparable between groups.»
  6. A Machine Learning Approach to the Differentiation of Functional Magnetic Resonance Imaging Data of Chronic Fatigue Syndrome (CFS) From a Sedentary Control (2020)

    Conclusion: «The logistic regression model performed on fMRI data significantly differentiated CFS from control with model accuracy of 80.9% on Day 1 before exercise and 76.1% on Day 2 during the period of post-exertional malaise.»
  7. Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome (2019)

    Conclusion: «ME/CFS patients with elevated blood lactate at rest may be at higher risk for more severe PEM.»
  8. Unexplained exertional intolerance associated with impaired systemic oxygen extraction (2019)

    Conclusion: «We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.»

    Article by Health Rising: Poor Oxygen Extraction is Contributing to Exercise Intolerance in Chronic Fatigue Syndrome (ME/CFS)
  9. Reproducibility of Measurements Obtained During Cardiopulmonary Exercise Testing in Individuals With Fatiguing Health Conditions – A Case Series (2019)

    Conclusion: «Nondisabled clients and clients with MS and HIV reproduced or improved in their volume of oxygen consumed (VO2), workload (WL), heart rate (HR), and minute ventilation (VE) at ventilatory anaerobic threshold (VAT) and at peak exercise (except peak WL and VE for the individual with HIV). Neither individual with ME/CFS reproduced VO2, WL, HR, or VE at VAT within literature estimates.»
  10. Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome (2019)

    Conclusion: «In conclusion, previous exercise deteriorates physical performance and increases [Laa] during exercise in patients with ME/CFS while it lowers [Laa] in healthy subjects.»
  11. Chronotropic Intolerance: An Overlooked Determinant of Symptoms and Activity Limitation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? (2019)

    Conclusion: «This literature synthesis supports the presence of abnormally blunted HR responses to activity in people with ME/CFS, at both maximal exertion and submaximal VAT.»
  12. Whole blood human transcriptome and virome analysis of ME/CFS patients experiencing post-exertional malaise following cardiopulmonary exercise testing (2019)

    Conclusion: «Although ME/CFS patients showed significant worsening of symptoms following exercise versus controls, with 8 of 14 ME/CFS patients showing reduced oxygen consumption (VO2) on day 2, transcriptome analysis yielded only 6 differentially expressed gene (DEG) candidates when comparing ME/CFS patients to controls across all time points.»
  13. Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2019)

    Conclusion: «The decrease in WR (work rate) at VT (ventilatory threshold) of 6.3-9.8% on the 2nd day of consecutive-day CPET may represent an objective biomarker that can be used to assist with the diagnosis of ME/CFS.»
  14. Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2018)

    Conclusion: «The second CPET measures changes in energy production and physiological function, objectively documenting the effects of post-exertional malaise.»
  15. Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study (2017)

    Conclusion: «These results suggest that exercise exhibits a different physiological response in MS and CFS/ME, demonstrating repeated cardiovascular exercise testing as a valid measure for differentiating between fatigue conditions.»
  16. A Pair of Identical Twins Discordant for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Differ in Physiological Parameters and Gut Microbiome Composition (2016)

    Conclusion: «Results suggest dysfunctional immune activation in ILL following exercise and that prokaryotic viruses may contribute to mucosal inflammation and bacterial dysbiosis. Therefore, a two-day CPET and molecular analyses of blood and microbiomes could provide valuable information about ME/CFS, particularly if applied to a larger cohort of monozygotic twins».
  17. Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (2015)

    Conclusion: «Upon exercise challenge, there were significant changes in the abundance of major bacterial phyla in the gut in ME/CFS patients not observed in healthy controls. In addition, compared to controls clearance of bacteria from the blood was delayed in ME/CFS patients following exercise.»
  18. Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO2peak indicates functional impairment (2014)

    Conclusion: «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.»
  19. Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome (2014)

    Conclusion: «Low oxygen uptake by muscle cells causes 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 argues against deconditioning as a cause for physical impairment in these patients.»
  20. Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome (2013)

    Conclusion: «Multivariate analysis showed no significant differences between control participants and participants with CFS for test 1. However, for test 2, participants with CFS achieved significantly lower values for oxygen consumption and workload at peak exercise and at the ventilatory or anaerobic threshold. Follow-up classification analysis differentiated between groups with an overall accuracy of 95.1%.»
  21. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity (2010)

    Conclusion: «At both exercise tests the 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.»
  22. Postexertional malaise in women with chronic fatigue syndrome (2010)

    Conclusion: «The results of this study suggest that PEM is both a real and an incapacitating condition for women with CFS and that their responses to exercise are distinctively different from those of sedentary controls.»
  23. Diminished Cardiopulmonary Capacity During Post-Exertional Malaise (2007)

    Conclusion: «In the absence of a second exercise test, the lack of any significant differences for the first test would appear to suggest no functional impairment in CFS patients. However, the results from the second test indicate the presence of a CFS related post-exertional malaise. It might be concluded then that a single exercise test is insufficient to demonstrate functional impairment in CFS patients. A second test may be necessary to document the atypical recovery response and protracted malaise unique to CFS».
  24. Chronic fatigue syndrome: new evidence for a central fatigue disorder (2003)

    Conclusion: «The significant differences between patients with CFS and healthy controls that we observed in several key CNS 5-HT and dopaminergic modulators, assuming that they are indeed reflective of brain 5-HT and dopamine levels, suggest that central neural mechanisms may contribute to the increased perception of effort and impaired exercise tolerance in CFS.»
Short film about PEM from the ME Association in Rogaland, Norway

Learn more

  1. Characterization of Post-Exertional Malaise: Findings from a new publication for NIH (2020/12)
    Lead author Barbara Stussman and co-author Dr. Brian Walitt
  2. PEM – strategies for determining and managing the cardinal symptom of ME/CFS (2020/10)
    Prof. Betsy Keller, Ithaca College, USA
  3. Pathophysiology of Exercise Intolerance in Chronic Fatigue Syndrome (2020/10)
    David M. Systrom, MD, Director of the Massachusetts General Hospital Cardiopulmonary laboratory, Boston, Massachusetts. Assistant Professor of Medicine at Harvard Medical School
  4. ME/CFS, CPET, PEM, COVID, GET and more (2020/08)
    Prof. Christopher R. Snell, Pacific Fatigue Laboratory, California, USA
  5. Pathophysiology of Exercise Intolerance in Chronic Fatigue Syndrome (2020/05)
    Dr. David M. Systrom (please see no. 3)
  6. Why Working out Doesn’t Work. Answers from 20 years of cardiopulmonary exercise testing (CPET) in ME/CFS (2019/12)
    Prof. Todd Davenport, prof. Mark VanNess and Director Staci Stevens (please see no. 15)
  7. PEM – ergospirometri-testing og mestringsstrategier for å unngå PEM (2019/12)
    Prof. Betsy Keller, PhD, Ihaca College, New York
  8. Understanding Graded Exercise Therapy for ME/CFS (2019/11)
    Dr. Chris Snell, prof. Mark VanNess, prof. Brian Hughes, prof. Jonathan Edwards and Director Staci Stevens (please see no. 15)
  9. Pathophysiology and treatment of exertional intolerance in ME/CFS: insights from cardiopulmonary exercise testing (2019/04)
    Dr. David M. Systrom (please see no. 3)
  10. Post Exertional Malaise in ME/CFS patients (2019/01)
    Katarina Lien, MD and PhD student, University of Oslo
  11. Advancements in ME/CFS Research (2018/07)
    Dr. David M. Systrom (please see no. 3)
  12. Inducing Post Exertional Malaise: A look at the research evidence (2015/07)
    Dr. Peter Rowe, Professor of Pediatrics, John Hopkins Hospital, USA
  13. Post Exertional Malaise: History, Characteristics, Evidence (2015/06)
    Dr. Lily Chu, Stanford University, USA
  14. Making the case for clinical exercise testing in CFS/ME research and treatment (2012/09)
    Prof. Christopher R. Snell, Pacific Fatigue Laboratory, California, USA
  15. MECFS Alert Episode 32 (2012/08)
    Staci Stevens, MA in exercise physiology. Director of the Pacific Fatigue Lab, Founder and Director of Workwell Foundation, Ripon, California, USA

The battle for truth

In light of Norway’s psychosomatic approach to ME/CFS, I’ll finalize with a recent quote by Prof. Vegard Bruun Wyller (the Norwegian Sr. author of the retractred music therapy study, and who’s now involved with the planned trial of the Lightning Process):

“Being interested in research is also about being open for the truth to be different from what you think.”

Exactly! This applies to the Norwegian Health Authorities, prof. Wyller, MDs and LP-activists as well.

Thank you for reading, and a big thank you to Jørn Tore Haugen for making the summaries.

Sissel Sunde

Jørn Tore Haugen: @jornt_h

One thought on “Energy failure in ME/CFS

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