Nijs, J., De Meirleir, K. D., Meeus, M., McGregor, N. R. and P. Englebienne. 2004. Chronic Fatigue Syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Medical Hypotheses 62: 759-765.
This most welcome article seeks to explain a phenomena that appears almost unique to CFS but which I believe is too little addressed in the literature - the intolerance that CFS patients display to vigorous or sometimes any exercise. The authors – posting from Belgium and Australia – note that not only is this phenomena not found in most disorders, it is not even normally found in fatigue-associated disorders such as depression, rheumatoid arthritis, lupus or multiple sclerosis.
The authors suggest that three mechanisms may limit CFS patients ability to exercise.
(1) A Channelopathy – A channelopathy or series of channelopathies resulting from RNase L fragmentation could lead to muscle weakness and/or hypoglycemia. When the RNase L enzyme breaks up it produces fragments (see A Channelopathy?) containing amino acid motifs that appear capable of interacting with the ABC transporters that control the flow of ions into and out of the cell. The sulfonylurea receptor, in particular, is interesting because it opens or closes based on ATP levels in the cell. (This implies, I believe, that this receptor could be dysfunctional not simply because of RNase L fragmentation but also because of the theorized low ATP levels found in CFS patients.)
Dysfunctional SUR receptors could lead to high losses of intracellular potassium and magnesium. A recent study provides ‘preliminary evidence’ that such occurs in at least a subset of CFS patients. Reduced magnesium levels are well known causes of muscle weakness and could be responsible for the reduced maximal oxygen intake (VO2 max) found in some CFS patients. Because the SUR 1 receptors play a role in glucose induced insulin secretion, they could be implicated in the transient hypoglycemia sometimes seen in CFS patients as well.
(2) Disrupted muscle cell production – RNase L has recently been shown to participate (via its regulation of mRNA) in muscle cell maturation. If the RNase L dysregulation thus far seen in immune cells extends to muscle cells then difficulty during exercise would be likely. (Only PBMC's have been tested for RNase L fragmentation. That RNase L fragmentation occurs in only a portion of PBMC's (monocytes, macrophages) perhaps argues against finding it in other, very different cell types?)
The authors note RNase L dysregulation is implicated in both of the mechanisms listed above. Next they propose a scenario explaining the maintenance of RNase L fragmentation. First they note that mycoplasma infections are frequently seen in CFS patients and that the phagocytic response mycoplasma's induce in monocytes, neutrophils and T-cells results in increased production of a protease, elastase, which has been implicated in RNase L fragmentation. The increased rates of apoptosis found in cells with RNase L fragmentation results, in turn, in the increased production of two apoptotic and/or inflammatory proteases (calpain, elastase) able to cause RNase L fragmentation. Mycoplasma infections, in short, appear able to initiate a vicious circle involving RNase L fragmentation, apoptosis and elastase and calpain production. A recent study documented that CFS patients with mycoplasma infections do, in fact, exhibit higher levels of RNase L fragmentation than those not infected with mycoplasma.
(3). Protein kinase R (PKR) dysfunction – An upregulation of the PKR arm of the IFN induced innate immune defense system presents another possible explanation of exercise intolerance in CFS. As with RNase L, PKR is first ‘woken up’ by type I IFN’s and then is activated by the presence of certain types of dsRNA (and other agents.) PKR activity is upregulated in many CFS patients.
PKR is a primary activator of a compound, nitric oxide (PKR – IxB – NF-kB – iNOS – NO), that is possibly central to the dysregulations found in CFS. High NO levels could cause increased oxidative stress, low blood pressure upon standing, decreased blood flow to the muscles during exercise and impaired oxidative metabolism (energy production) in the cells. CFS patients appear to have high NO levels at rest.
The authors speculate NO induced vasodilation of the blood vessels during exercise could result in decreased blood flow to the muscles and reduced exercise capacity in CFS patients. High levels of NO during exercise could also inhibit the post exercise recovery period and be responsible for the unusual post-exercise exacerbation of symptoms seen in CFS.
(4). High mitochondrial NO levels in CFS patients could also inhibit oxidative metabolism causing decreased ATP production and reduced aerobic production as well.
(5). Excess NO could also induce exercise induced fatigue by interfering with the ryanodine receptors responsible for muscle contraction.
The authors noted that the source of the elevated NO levels is unclear. They indicate Mycoplasma fermentans - which is commonly found in CFS - produces a substance called MALP-2 (macrophage activating lipopeptide) that stimulates macrophages to secrete NO. This mycoplasma also activates a portion of the immune system (complement) that was recently shown to be activated in CFS patients during exercise. (Interestingly the part of the complement system activated in CFS patients induces the production of a protease, elastase, able to fragment RNase L) Another pathogen commonly found in CFS patients, Chlamydia pneumoniae, and other viruses, are able to trigger NO production via NF-kB. Chronic infections of either type could lead to high NO levels.