Understanding neuromuscular disorders in chronic fatigue syndrome

Central fatigue

Some physiological studies using the twitch interpolation technique and analyzing the maximal voluntary contraction cannot support the hypothesis of central fatigue in patients with ME/CFS^18,19. By contrast, numerous studies support the existence of central fatigue in these patients. Kent-Braun et al.²⁰ showed that the voluntary contraction of the tibialis muscle during maximal isometric exercise was lowered. In patients with post-infectious CFS, Sacco et al.²¹ reported a reduced amplitude of motor potentials evoked by TMS of the motor cortex in the biceps brachii muscle. The authors also reported an increased interpolated twitch amplitude during sustained fatiguing efforts in patients with ME/CFS. The same observations were made by Schillings et al.²². Davey et al.²³ correlated day-to-day changes in ME/CFS symptomatology with the changes in simple reaction times (SRTs) and movement times of myopotentials evoked in muscles by TMS of the motor cortex, and corticospinal excitability was assessed by measuring the threshold TMS intensity. The authors reported slowed SRTs and increased threshold intensity, supporting the existence of a deficit in motor preparatory cortical areas. Siemionow et al.²⁴ reported a modification of the central motor command to muscles during isometric handgrip and measured an increased relative power of electroencephalography theta frequency band in patients with ME/CFS compared with healthy volunteers. These observations suggest that ME/CFS pathology may be associated with an altered central nervous system command to muscles.

Perception of effort and pain seems to be accentuated in patients with ME/CFS. This was previously reported by Sacco et al.²¹ and more recently confirmed²⁵. The group III or IV metabosensitive muscle afferents present in all skeletal muscles are strongly activated by the oxygen free radicals¹⁶, a situation amplified in patients with ME/CFS^5,6. It is tempting to speculate that increased activation of muscle afferents in patients with ME/CFS could result in an accentuated perception of effort and pain (myalgia). The key role played by these muscle afferents in central fatigue (muscle wisdom phenomenon) could also explain the numerous observations of a diminished central activation, documented in ME/CFS^20–24.

Peripheral fatigue

Delayed recovery from fatiguing exercise in patients with ME/CFS may be due to peripheral muscle fatigue^9,26. During incremental cycling leg exercise approaching the maximal oxygen uptake (VO₂), marked alterations of myopotentials in response to direct muscle stimulation (M-wave) have been observed in a number of patients with ME/CFS^5–8. These M-wave changes began early in exercise and culminated at the end of a 30-min recovery. This suggests the existence of peripheral fatigue due to impaired muscle membrane excitability. Similar M-wave alterations are absent in healthy subjects, for whom the amplitude of myopotentials either does not vary or even increases with the incremental pedaling force⁵.

Reduced ionic fluxes through the muscle membrane

Alteration of ionic fluxes through the sarcolemma could explain the altered muscle membrane excitability reported in patients with ME/CFS. In healthy subjects, muscle biopsies demonstrated a physiological contraction-induced loss in myoplasmic potassium (K⁺) concentration²⁷. This potassium outflow is detectable in plasma, and the kinetics of plasma K⁺ increase during and after an incremental exercise is well known²⁸. A study by Fulle et al.²⁹ confirmed the presence of alterations in ryanodine channels and a deregulation of Na⁺/K⁺ and Ca²⁺-ATPase pumps in the membranes of sarcoplasmic reticulum in patients with ME/CFS. To explain their data, Fulle et al.³⁰ suggested that the deregulated pump activities could result from an increased fluidity of the sarcoplasmic reticulum membrane in these patients.

Increased production of reactive oxygen species

Several studies in patients with ME/CFS have examined changes in resting blood oxidant–anti-oxidant status and reported lower vitamin E concentration and higher levels of oxidized LDL, thiobarbituric acid reactive substances (TBARS), and malondialdehyde (MAL)^31–33. In biopsies of vastus lateralis muscle of patients with ME/CFS, Fulle et al.³⁰ detected oxidative damage to DNA and lipids and increased activity of intracellular anti-oxidants (catalase, glutathione peroxidase, and transferase). Other authors also found a correlation between musculoskeletal symptoms and an accentuated lipid peroxidation at rest in patients with ME/CFS^33,34. Plasma markers of oxidative stress are the TBARS, a marker of lipid peroxidation, and reduced ascorbic acid, an endogenous anti-oxidant^{5–7,31–34}.

In healthy subjects, exercise induces modest oxidative stress^5,35,36, whereas marked exercise-induced production of ROS has been found in patients with ME/CFS^5–7. The muscle production of oxygen free radicals is proportional to that of VO₂^35,36. From several reports^5,37,38, VO₂ measurement in exercising patients with ME/CFS indicated a normal aerobic function; indeed, their maximal VO₂ was in the normal range. However, a recent study³⁹ showed that, perhaps because of PEM, patients with ME/CFS were unable to reproduce cardiopulmonary exercise testing during a second test. An in vitro study in skeletal muscle cell culture⁴⁰ showed that, after electrical pulse stimulation mimicking PEM, patients with ME/CFS, compared with normal subjects, had no increase in AMPK phosphorylation, a defect of glucose uptake, and a reduction of interleukin-6 (IL-6) secretion, highlighting the reality of lowered metabolic performance of muscle cells during PEM. A recent study by Richardson et al.⁴¹ proposed using the weighted standing time as a proxy for PEM severity in patients with ME/CFS.

An inhibitory action on Na⁺-K⁺ pump activity is exerted by increased production of ROS during exercise¹¹ and this reduces muscle membrane excitability and potassium outflow. Published^5–8 and unpublished observations have noted that the magnitude of altered muscle membrane excitability (reduced M-wave amplitude) is proportional to the reduction of exercise-induced potassium outflow and to the magnitude of oxidative stress in patients with ME/CFS. Moreover, in 42% of the 69 patients with ME/CFS, PEM was associated with post-exercise alterations of muscle membrane excitability.

Reduced heat shock protein production/expression

The HSPs protect cells against the deleterious effects of ROS produced during exercise^42,43, reducing the generation of ROS through the activation of anti-oxidants. The oxidant levels, in turn, increase the level of plasma HSP⁴³. In patients with ME/CFS, the responses of plasma HSP27 and HSP70 to exercise can be delayed and often reduced, and resting levels of plasma HSP70 are lower in these patients than in healthy volunteers⁶. The lack of HSP response to exercise might explain the augmented oxidative stress measured in these patients. As already suggested⁷, a downregulation of HSP production in some individuals could be caused by the repetition of exercise bouts at high energetic levels. As cited above, the activation of the group III or IV muscle afferents triggers the HSP production in working and resting muscles as well as in the brain and different organs¹⁷. It may be hypothesized that the prolonged activation of these muscle afferents by the oxidative stress could induce a reduction of HSP production in patients with ME/CFS. Further studies, including in high-intensity sport programs and military training, are needed to show that the repetition of exercise bouts at high levels might depress the expression of the inducible factors of HSP However, HSP malfunction was also reported in different pathologies and may have origins other than the repetition of stressors. Thus, in patients with multiple sclerosis and systemic lupus erythematosus, Elfaitouri et al.⁴⁴ measured an IgM to specific cross-reactive epitopes of human HSP60 compatible with infection-induced autoimmunity. HSP dysfunction was also reported in patients with chronic fatigue in primary Sjögren’s syndrome⁴⁵. Because antibodies to a microbial HSP60 may cross-react with human HSP60⁴⁶, it may be that infectious diseases often reported in patients with ME/CFS alter their HSP function.