I am trying to get my head around the question of whether ME could be a metabolic problem, as suggested by the 'something in the blood' findings by several different researchers, and by the problems with pyruvate dehydrogenase possibly blocking or reducing complete breakdown of glucose, and by the seahorse oxygen uptake studies. Or, as @Jonathan Edwards suggests here, a signalling problem involving some sort switching off coming from the brain that might better explain PEM. This discussion has cropped up on several threads recently, and rather than derail them further, I've decided to gather the information and ideas here. Relevant thread discussions: Blog: 'Summary so far of "Something in the blood"' by Simon McGrath US NIH: Responses to NANDS Request for Information: How to advance ME/CFS Research Discussed further here, here and here and onward. There is also the question of how much activity a person with ME can sustain day after day compared with a healthy person, as discussed here: Andy's attempt to create a reasonable descriptive model of ME which again raises the question of whether there is a problem metabolically in creating enough energy for activity above basal metabolic level, and how much we can exceed our sustainable level before PEM, and whether PEM is about lack of energy for basal functions, leading to a wide range of horrible body wide symptoms, or whether it is signals from the brain that are setting off PEM symptoms, or something else.