Action for M.E.’s annual general meeting (AGM) was held in London on November 8th, 2013. More than 70 patients, carers, health professionals, researchers, staff and trustees attended the conference where they heard presentations on the state of ME/CFS research.
Professor Julia Newton of Newcastle University gave a presentation titled “Understanding Muscle Dysfunction in M.E./CFS.” Professor Newton is the Dean of Clinical Medicine at Newcastle University. She has a background in liver and renal disease and is currently investigating autonomic dysfunction in ME/CFS.
Professor Newton began her lecture by introducing how her group investigated muscle function in patients with ME/CFS. Newton’s group used MRIs to assess acid accumulation in the muscle tissue of patients during intial and repeat exercise. They found a “huge” accumulation of acid in skeletal muscle tissue, both during and between bouts of exercise, indicating a loss of efficiency in muscle function.The experiments also revealed other problems with bioenergetic function, such as a significant reduction in anaerobic threshold in patients with ME/CFS compared to normal controls. (It has long been proposed that ME/CFS patients shift to anaerobic metabolism faster than healthy people. Anaerobic metabolism, by not requiring oxygen, is less efficient than aerobic metabolism, and leads to the accumulation of lactic acid. It also leads to the production of ammonia, which can cause confusion and disorientation when taken up by brain tissue. Dr. Cheney proposed that the CNS problems experienced by people with ME/CFS could be attributed to the toxic effects of ammonia in the brain )
One of the things that Newton’s group noticed during the experiments was that there were two distinct types of muscle abnormalities patients with ME/CFS: those who depleted their phosphocreatine (also known as creatine phosphate) during exercise, and a second group that did not deplete phosphocreatine and didn’t accumulate acid within their muscles.
Phosphocreatine plays an important role in regenerating ATP in muscle tissue after exercise. It transfers a high-energy phosphate to ADP. The products of this reaction are ATP and creatine. Phosphocreatine is obtained from two sources: meat and internal production by the liver and kidneys, which is why one of the symptoms of liver and kidney disease is profound fatigue. Patients with these illnesses cannot generate phosphocreatine, leading to a loss of ATP and a subsequent reduction in cellular energy.
The second stage of Newton’s research was to examine muscle tissue in a laboratory setting. The patients who participated in the MRI study contributed muscle cells via biopsy. The researchers then grew the cells into muscle tubules in order to see what happens within those cells in response to exercise. Specifically, they were looking at how AMP kinase was activated, as well as production of lactate dehydrogenase.
AMP kinase is an enzyme that regulates metabolic energy production in skeletal muscle cells, as well as in fatty tisue, liver, and certain pancreatic cells. Lactate dehydrogenase is an enzyme that converts pyruvate to lactate when oxygen is absent (anaerobic metabolism). Lactate dehydrogenase is medically significant because it is released during tissue damage, which means it serves as a marker of injuries and disease.
Newton’s team also looked at glucose uptake and the expression of IL-6, a pro-inflammatory cytokine which is secreted by muscle cells. Glucose, a sugar, is a substrate for AMP kinase, and serves as an indicator of energy metabolism in muscle cells, while IL-6 is associated with muscle contractility.
By electrically stimulating the muscle cells grown in the laboratory. the researchers were able to examine the secretion of these various molecules during exercise. They found that in controls, AMP kinase is activated and peaks at 16 hours, whereas in patients with ME/CFS AMP kinase is not activated, indicating a dysregulation of energy production.
Newton’s group also discovered that glucose uptake is enhanced during exercise in controls (with the administration of insulin), whereas in patients with ME/CFS glucose uptake is not enhanced by exercise. (A failure to utilize glucose is the metabolic defect associated with type 2 diabetes. Exercise is recommended to diabetic patients to help glucose uptake.) The implication is that in ME/CFS patients, the normal physiological benefits of exercise, such as increasing energy through enhanced glucose uptake, are not experienced. (It should be mentioned here that the principal source of energy for the brain is glucose. A reduction in glucose supply to the brain leads to impairments in psychological procsses requiring effort, such as making decisions.)
Professor Newton concluded her presentation with a novel treatment idea. If lactic acidosis in skeletal tissue can be corrected, many symptoms common in ME/CFS patients – fatigue, anxiety, nausea, irregular or rapid heart rate, hypotension – could be eliminated. She proposed an analog of DCA (dichloroacetate), a drug currently used in cancer therapies to reduce tumor growth, as a possible “fast-track” treatment for ME/CFS. In addition to its role in cancer cell destruction, DCA modifies the pathways within muscle cells leading to lactic acid accumulation and muscle dysfunction, moving them towards normal muscle function.