Hollingsworth KG, Jones DEJ, Taylor R, Blamire AM, Newton JL


Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK


Impaired skeletal muscle metabolism is recognized in chronic fatigue syndrome (CFS). This study examined the relationship between skeletal and cardiac muscle function and symptoms on standing in CFS using magnetic resonance spectroscopy (MRS) and impedance cardiography.

Materials and Methods

Phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio by cardiac MRS, PCr/ADP and proton efflux by muscle MRS were performed in 12 CFS (Fukuda) and 8 controls. Head up tilt (HUT) and cardiac contractility (left ventricular work index, LVWI) (n=64 CFS and matched controls) were found. Fatigue impact was accessed by Fatigue Impact Scale and orthostatic symptoms by Orthostatic Grading Scale (OGS).


Cardiac PCr/ATP correlated with measures of muscle bioenergetic function (half-time PCr recovery [kappa = -0.71, P=0.005] and half-time ADP recovery [kappa = -0.60, P=0.02]) suggesting that the muscle and cardiac bioenergetic function correlate in CFS. Four of 12 (33.3%) CFS patients had PCr/ATP values consistent with significant cardiac impairment. Those with impaired cardiac energy metabolism had significantly reduced maximal and initial proton efflux rates (P<0.05). Cardiac PCr/ATP ratio correlated with myocardial contractility (LVWI) in response to standing (P=0.03). On HUT, LVWI on standing was significantly higher in CFS (P=0.05) with symptoms on standing (OGS) occurring in 61/64 (95%) (vs. 25/64 [39%] controls; P<0.0001). OGS scores were significantly higher in those with abnormal LVWI responses to standing (P=0.04), with the LVWI on standing correlating with OGS scores (r²=0.1; P=0.03). HUT was positive in 19 (32%).


Skeletal muscle and cardiac bioenergetic abnormalities associate in CFS. Cardiac bioenergetic metabolism associates with increase in cardiac contractility on standing. Haemodynamic assessment in CFS is well tolerated and safe with a high diagnostic yield comparable with unexplained syncope.


European Journal of Clinical Investigation, 2010 Jul; 40(7): 608–1

Comment by ME Research UK

The University of Newcastle houses the most active ME/CFS biomedical research group in Europe, and one of the most active in the world. Since 2006, with funding from ME Research UK and partners, the group has come up with a range of fascinating findings and continues to push at the boundaries.

In the past, the group has found a worsening of symptoms with orthostatic stresses (such as standing) and an impairment of “skeletal muscle bioenergetics” in many patients. Because of these findings, Prof. Newton, Prof. Jones and their colleagues began to hypothesise that the impaired muscle function they had observed previously was not confined only to skeletal muscle, but in fact represented a larger, systemic abnormality. If this were the case, then the muscle of the heart could also be affected, and this might explain the impaired cardiovascular function seen in many patients on standing, as well as the symptoms experienced by many. In addition, it would provide pointers towards potential treatments.

To explore these issues, the researchers, in conjunction with senior physicist Dr Kieren Hollingsworth, examined skeletal (lower leg) and heart muscle using magnetic resonance spectroscopy (MRS), a technique that provides a non-invasive window into cellular metabolism deep within the tissues.

In skeletal muscle, measurements of maximum voluntary contractions were made during exercise, while heart muscle was assessed using MRS imaging of cardiac high-energy phosphate metabolism, including phosphocreatine and ATP. Magnetic resonance imaging of the heart was also carried out.

Another experiment tested the diagnostic usefulness of measuring haemodynamic and cardiac function in a large group of 64 ME/CFS patients and matched controls, who all underwent formal autonomic assessment in the cardiovascular laboratory. The participants’ haemodynamic responses to prolonged standing were examined by Head Up Tilt using a tilt table, during which measurements of cardiac function were made; these included the cardiac index (output of the heart per minute) and left ventricular work index (the amount of work the left ventricle must perform to pump blood each minute, and considered to be the best impedance measure of myocardiac contractility).

Overall, the study demonstrated that “bioenergetic abnormalities” could indeed be found both in skeletal and cardiac muscle, with a correlation between the two suggesting the existence of linked underpinning mechanisms. These findings accord with the researchers’ original hypothesis.

In addition, orthostatic symptoms (problems standing up) were prevalent in the patients, and these were related to the amount of work the heart had to exert (significantly more in patients than controls). There were also correlations between cardiac bioenergetics and cardiovascular responses to standing. The researchers say that they cannot yet tell from these MRS experiments whether impairments of skeletal muscle or cardiac energy metabolism are due to primary mitochondrial defects or to alterations in muscle blood flow, although they suggest that the latter is more likely.

Interestingly, the Head Up Tilt test (which simulates prolonged standing) was again found to be a revealing and sensitive test of abnormalities in ME/CFS patients. Yet, this is the very assessment tool that the NICE clinical guideline of 2007 (section actively discourages clinicians from using to aid diagnosis.

As the research group says in its published paper, given that their study confirms a comparatively high diagnostic rate in ME/ CFS, particularly in those with a history of fainting, “we would recommend therefore that referral for cardiovascular testing, including Head Up Tilt testing, is encouraged in those where symptoms on standing are predominant”. Since most ME/CFS patients have symptoms on standing, particularly problems with standing still, it is surely time for NICE actively to recommend cardiovascular testing.

This essay is an extract from our article (pdf 1 MB) in the Spring 2011 issue of Breakthrough.