TGI Friday! Our weekly roundup of recently published ME/CFS abstracts | 2 May 2014

May 2, 2014

From Experimental Physiology, February 2014 (e-published 18 October 2013).

Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects.

Pollak KA(1), Swenson JD, Vanhaitsma TA, Hughen RW, Jo D, Light KC, Schweinhardt P, Amann M, Light AR*.
1*) University of Utah, Department of Anesthesiology 3C444 SOM, 30N 1900E, Salt Lake City, UT 84132, USA.



What is the central question of this study? Can physiological concentrations of metabolite combinations evoke sensations of fatigue and pain when injected into skeletal muscle? If so, what sensations are evoked? What is the main finding and its importance?

Low concentrations of protons, lactate and ATP evoked sensations related to fatigue. Higher concentrations of these metabolites evoked pain. Single metabolites evoked no sensations. This suggests that the combination of an ASIC receptor and a purinergic P2X receptor is required for signalling fatigue and pain. The results also suggest that two types of sensory neurons encode metabolites; one detects low concentrations of metabolites and signals sensations of fatigue, whereas the other detects higher levels of metabolites and signals ache and hot.

The perception of fatigue is common in many disease states; however, the mechanisms of sensory muscle fatigue are not understood. In mice, rats and cats, muscle afferents signal metabolite production in skeletal muscle using a complex of ASIC, P2X and TRPV1 receptors. Endogenous muscle agonists for these receptors are combinations of protons, lactate and ATP. Here we applied physiological concentrations of these agonists to muscle interstitium in human subjects to determine whether this combination could activate sensations and, if so, to determine how the subjects described these sensations.

Ten volunteers received infusions (0.2 ml over 30 s) containing protons, lactate and ATP under the fascia of a thumb muscle, abductor pollicis brevis. Infusion of individual metabolites at maximal amounts evoked no fatigue or pain. Metabolite combinations found in resting muscles (pH 7.4 + 300 nm ATP + 1 mm lactate) also evoked no sensation.

The infusion of a metabolite combination found in muscle during moderate endurance exercise (pH 7.3 + 400 nm ATP + 5 mm lactate) produced significant fatigue sensations. Infusion of a metabolite combination associated with vigorous exercise (pH 7.2 + 500 nm ATP + 10 mm lactate) produced stronger sensations of fatigue and some ache. Higher levels of metabolites (as found with ischaemic exercise) caused more ache but no additional fatigue sensation. Thus, in a dose-dependent manner, intramuscular infusion of combinations of protons, lactate and ATP leads to fatigue sensation and eventually pain, probably through activation of ASIC, P2X and TRPV1 receptors.

This is the first demonstration in humans that metabolites normally produced by exercise act in combination to activate sensory neurons that signal sensations of fatigue and muscle pain.

From Fatigue: Biomedicine, Health & Behavior, e-published 23 April 2014.

The delayed fatigue effect in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Megan A. Arroll, Elizabeth A. Attree, John M. O'Leary & Christine P. Dancey
School of Psychology, The Chronic Illness Research Team, University of East London, London, UK



Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, long-term condition characterised by extreme fatigue (worsened by exertion), muscle and joint pain, and sleep disturbance. Post-exertional fatigue has been demonstrated previously following physical exercise, but not from mental exertion alone.


The aim of this exploratory study was to assess the ‘delayed fatigue effect,’ in this instance fatigue two days post-challenge, following a cognitively fatiguing task.


Thirty-two participants (23 women; mean age 44, SD = 11.24; mean illness duration nine years, SD = 7.32) completed the Cambridge Neuropsychological Test Automated Battery, which acted as the cognitive challenge. Self-report measures were also completed that
assessed fatigue (Multidimensional Fatigue Inventory; MFI), and anxiety and depression (Hospital Anxiety and Depression Scale; HADS) pre- and two days post-testing.


Significant differences were found between pre- and post-test measures in three MFI sub-scales of fatigue (general, mental, and physical) and on the depression scale of the HADS. However, there were no significant changes in motivation, activity level, or self-reported
anxiety scores.


These findings are suggestive of post-exertional symptom exacerbation following mental effort. This may have implications for working environments that present cognitive demands to individuals with ME/CFS.

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