Reprinted with the kind permission of Cort Johnson and Health Rising.
By Cort Johnson
“New data collectively supports the presence of specific critical points in the muscle that are affected by free radicals.” Fulle et. al.
A group of pioneering Italian researchers have been studying the muscles of people with ME/CFS – a rather lonely task – for over 15 years. Hailing from the Universitá di Perugiá in Perugia, Italy, they’ve poured out muscle studies in ME/CFS every couple of years. Why do they keep to their rather lonely task? It’s probably because they keep getting intriguing findings.
In very broken English, the Italian researchers laid out their conception of chronic fatigue syndrome (ME/CFS).
With the exercise intolerance present, muscles present such an intriguing area for ME/CFS. The authors believe the muscle problems found in ME/CFS look more like aging than anything else.
(If that’s true there must be a lot of aging going on in this disease. Many times I’ve been overtaken on my short walks by quite elderly people walking by at what seemed to me to be a remarkably rapid click.)
Just as in the elderly, the number and size of muscle fibers in ME/CFS are reduced. Plus problems with calcium transport may be producing fatigue in both people with ME/CFS and the elderly.
The type of muscle fibers present may also be altered (fast-twitch muscles predominate) while basic contractile properties of the muscles remain intact. Those fast-twitch muscle fibers get fatigued more easily and require more energy.
The Culprit – Oxidative Stress?
The mitochondrial, muscle and free radical issues found in ME/CFS point a finger, these authors feel, at one culprit – oxidative stress. (In the brain, Dr. Shungu is pointing his finger in the same direction.)
With all the inconsistencies in ME/CFS research, it’s rather reassuring that every study – whether done in the brain, muscles or blood – that’s looked for oxidative stress in ME/CFS has found it elevated.
Reactive oxygen species (ROS) or free radicals are produced in abundance during energy production and particularly during exercise. Our cells usually easily mop up those free radicals, but damaged mitochondria can produce enough free radicals to overwhelm our anti-oxidant system. If things get bad enough the cell may even die. Plus inflammation – a prime target in ME/CFS – can produce scads of oxidative stress as well.
At least three studies show that exercise abnormally increases levels of free radicals in this disease. One study suggested that those free radicals could be having real consequences: they were associated with impaired energy production in the muscles of people with ME/CFS. Plus, the membranes of the muscle cells – which free radicals love to nip at – appear to be damaged as well.
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Furthermore, indications of oxidative damage were found in 66 muscle biopsy specimens from ME/CFS patients. A study of the gene expression in the muscles of people with ME/CFS found altered expression of the genes involved in mitochondrial functioning, oxidative stress, and muscle structure and fiber type. All in all, it appears that ME/CFS patients’ rather weak antioxidant systems may not be keeping up with what appears to be a torrent of oxidative stress.
That oxidative stress could be damaging the mitochondria and the ability of the muscles to contract and produce energy. One study reportedly found that a group of ME/CFS patients with a severe infectious onset had the trifecta – high levels of free radicals, even at rest, their muscles were mostly dead to the world (didn’t respond to exercise) and had ion channel problems that may have affected the ability of their muscles to contract.
A exercise/gene expression study found similar evidence of a strange non-response to exercise:
Contrast the 50 genes that became activated during exercise in GWS and the one that got activated in ME/CFS and you get a picture of a moribund metabolic system that cannot rise to the occasion. That finding fits in well with evidence that the sympathetic nervous system also poops out during exercise.
Inflammation the Key?
Could it all come down to that ubiquitous bug-a-boo, inflammation? One review suggested that low grade inflammation plus chronically high levels of free radicals could explain the muscle fatigue so often seen in ME/CFS. A 2014 literature review found some evidence that exercise is producing immune changes in ME/CFS.
Nancy Klimas’s extensive sampling before, during and after exercise appears to have captured the process. That study found that a remarkable upregulation of inflammatory pathways occurs during exercise in ME/CFS, which is followed some hours later by a similar upregulation of pathways involved in oxidative stress and other processes. The inflammation comes first and produces, among other things, a dramatic increase in free radical production, which causes damage and almost certainly contributes to the PEM experienced.
This Italian group and some U.K. researchers have been carrying the torch for muscle damage in ME/CFS for over a decade. The results have been intriguing but have not yet lit the world on fire. Muscle studies in ME/CFS are still relatively rare.
Given enough funding, that could change soon. We have a new and potentially very powerful entry into the muscle field – one that has already been opening doors that have heretofore been closed. Ron Tompkins, the leader of the Open Medicine Foundation funded ME/CFS Collaborative Research Center at Harvard, is eager to dig deeper – much deeper – into ME/CFS patients’ muscles than has ever been done before. Another one of Ron Davis’s longtime comrades and collaborators, Tompkins has got the facilities he needs and has quickly gathered the collaborators needed to crack this area of ME/CFS wide open.
Tompkins has quickly managed to gather a rather remarkable team. Specialists in bioinformatics, muscle biopsies, muscle metabolism, proteomics, sepsis, medical genetics, inflammation, sleep and others are sprinkled throughout his team. Among others, Dr. Komaroff, Michael Van Elzakker (Vagus Nerve Hypothesis), David Systrom, Janet Mullington and Wenzhong Xiao have joined the team. One team member, Dr. Felsenstein MD, has been following some of her ME/CFS patients for over 20 years.
Tompkins, who has lead some of the biggest and longest NIH funded studies ever, clearly hasn’t had much trouble gathering outside researchers into his team. His problem is not finding good people to work on ME/CFS; rather, his problem will be gathering enough money to maximize their talent. Getting funding is not easy, but it’s actually far easier than gathering top talent: Tompkins’ problem is not a bad one to have.
Given enough funding, Tompkins and his team have the potential to blast open our understanding of the role problems in the muscles play. For me, with all the PEM that mild exercise brings, it’s hard to imagine that all the threads of ME/CFS research – the autonomic nervous system, metabolic, central nervous and immune system problems – don’t in some way meet in the muscles. They could provide a window into the heart of this disorder.
About the Author: Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on myalgic encephalomyelitis, chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising.