Taking the Next, er, Step


Exercise physiologists are becoming more engaged in finding the cause for the exercise intolerance in ME/CFS

First you document the problem, then you try to figure out what’s causing it.  At least three research groups have decided it’s time to move past documenting a messed up  energy production system in ME/CFS and to begin figuring what’s causing it. Over the next couple of months we’re going to see reports on cytokines and exercise, on lung issues and exercise and, in this study, on oxygen uptake and exercise.

Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome.Vermeulen RC, Vermeulen van Eck IW. J Transl Med. 2014 Jan 23;12(1):20. doi: 10.1186/1479-5876-12-20.

Follow the Oxygen Molecule

Maximal oxygen consumption reflects the aerobic and physical fitness of the individual. Wikipedia

oxygen molecule

Getting oxygen into the muscles is the key to being able to exercise vigorously

Past studies from Dr. Newton and others have been zeroing in on poor oxygen uptake by the muscles. Let’s take a quick look at oxygen and energy production.

Oxygen means  everything for exertion in humans. If you want to be able exercise vigorously you’ve got to get oxygen (and lots of it) into the mitochondria of your muscles. We get more oxygen into our blood by breathing more deeply and quickly, and then our hearts whip it to our muscles more quickly by beating faster and pumping out more blood.  If it all works right we’re pounding the pavement for our morning jog or hitting the tennis courts for our afternoon sets.

Something obviously has gone very wrong when simply a walk around the block wipes people with ME/CFS out.

Big Study

Over the course of five years Vermeulen’s clinic collected exercise data on 203 people with CFS (Fukuda) and 223 other fatigued (did not meet Fukuda) patients (called Chronic Fatigue Idiopathic). Everyone with CFS (Fukuda) or severe fatigue (CFI) in this Dutch ME/CFS clinic got to do  one exercise test to exhaustion. (Lucky them:) ). That made this study easily the biggest exercise study ever done in chronic fatigue syndrome.

The small control group (n= 18) included  men and women who were ‘physically active’ less than an hour a week.  (Somebody better acquainted with statistics and study design would know better how the small control group vs the large patient group affects the rigor of the results.)


Seventy percent of the  CFS and the CFI patients had significantly lower maximal oxygen uptake (VO2 max) at anaerobic threshold than the controls.  ‘Significantly lower’ did not mean a bit lower; the high probability scores (P<.008) indicated that oxygen uptake into the muscles was much lower in the fatigued group.

downward chart

Oxygen uptake by the muscles at anaerobic threshold was greatly reduced in about 2/3rds of the ‘chronic fatigue’ patients

For  example, the lowest muscle oxygen uptake achieved by the healthy controls at maximal workload was a very low 10 ml/100 mls, a value Vermoulen reported is found in heart failure..

The lowest O2 uptake by the CFI patients was almost half that (5.4 ml/100 mls), while  the lowest oxygen uptake by the ‘CFS’ (Fukuda) patients was less  than half that of the worst off control (4.4 ml/100 mls.) or similar to that found in (asymptomatic) HIV patients. That means that the muscles of that patient was receiving about 44% of the oxygen that the poorly functioning healthy control was.

The fact that the patients who met the Fukuda definition and who did not had similar VO2 max levels at anaerobic threshold suggested that simply being very fatigued was enough to result in low VO2 max scores.

The ME/CFS group, had a higher cardiac output relative to oxygen uptake, than the idiopathic CFS group appeared to suggest that their hearts were working harder in an attempt to compensate for the reduced oxygen uptake.

The Normal VO2 Max ME/CFS and CFI Group

About 30 percent of ME/CFS and the CFI had VO2 max results similar to those found in the healthy controls. (Oddly enough more ME/CFS patients (73.203 – 35%) than CFI (59/223 – 26%) did not have reduced VO2 max values.  The source of their fatigue lay elsewhere.  (But would their normal VO2 max levels remained normal in a second , repeat exercise test.)

Cause of the Cause?

If low oxygen uptake is responsible for the reduced exercise performance what is causing the low oxygen uptake?

The oxygen carrying capacity of the hemoglobin in the red blood cells that carries oxygen could be reduced. The lungs might not be pumping hard enough to get the oxygen into the blood in the first place. The heart might not be pumping fast enough and hard enough to get the blood to the muscles. The blood and oxygen might be getting to the muscles, but the muscles might not be picking it up.  Lastly, deconditioning  or lack of effort could be a factor.

This study found no reason to suspect that lung or heart problems or deconditioning or lack of effort played a role in the inability of  many people with CFS or CFI.

Instead the authors proposed that mitochondrial problems or immune issues were responsible and pointed to reduced VO2 max levels found in people with lupus in  1995. Three  followup studies  found that reduced aerobic metabolism was common on SLE.

The Autoimmune Connection

cortisol molecule

Several studies suggest reduced cortisol during exercise could play a role in similar exercise problems in some autoimmune disorders

Since cortisol plays a significant role in releasing energy for exercise, the authors of a 2004 study examined the effects of maximal exercise on cortisol production in rheumatoid arthritis and lupus.  Cortisol levels should rise in response to exercise, but they in both disorders they immediately fell 10%  during exercise and over 20% an hour later.  A later study  suggested that low cortisol in combination with increased cytotoxic T-cells helped  set the stage for RA. (Soon we’re going to review an ME/CFS paper suggesting that low cortisol in combination with immune factors could set the stage for many disorders including ME/CFS).

Unexpected decreases in cortisol (and IL-8 and heat shock proteins) in fibromyalgia during moderate exercise suggested a similar pattern may prevail there.

At one time cortisol was the most researched topic in chronic fatigue syndrome. Studies linking low cortisol output to reduced exercise capacity and altered immune functioning in these disorders suggest reviving it again might be a good idea.  (Cortisol levels were not reduced during a standardized exercise test in one study, but ACTH responsive was. )


The sheer size of this study would, one would think, effectively end the question whether metabolic abnormalities thwart energy production during exercise in ME/CFS, or whether deconditioning is a significant factor.  (Wyller’s recent study also suggested deconditioning was not a factor. In fact, it’s hard to think of any physiological study – although many have tried –  which has suggested that deconditioning is a significant factor in chronic fatigue syndrome.)

Vermeulen’s findings fit a  series of research results that are more and more fingering reduced oxygen uptake as a cause of the exercise problems in ME/CFS.  (He noted that Newton’s recent pH findings may fit his findings.) While people with autoimmune disorders and fibromyalgia do not typically experience the degree of exercise incapacity as ME/CFS (and light exercise is often recommended), similar reductions in VO2 max have been found, and may be tied to cortisol and immune abnormalities.

Satisfied that metabolic impairment is present, exercise physiologists are moving forward to try and discern its cause. At the March IACFS/ME conference Workwell’s exercise findings will focus on reduced ventilation and cytokines will be the focus of another exercise study.  We seem to be getting closer.


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