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“I had thought, it’s only about nine minutes of exercise, how much is going to change? A lot, as it turns out.” Dr. Mike Snyder – senior author of the study

How much could nine minutes of an exercise bout change in your body? Probably not that much, Dr. Snyder apparently thought. He, after all, can hop on his bike and pedal away without a second thought.  At most, he might feel achy and tired for a day or two.

38 people were exercised to exhaustion and then were given every “omics” test in the book.

But people with ME/CFS have a different perspective.  Too much “exercise” – make that activity – can produce a dazzling array of painful symptoms that can last days or more. In other words, it’s crystal clear to them that whether healthy people realize it or not, whatever exercise does, it must profoundly affect the body.

So, while the researchers at Stanford were surprised that a single bout of exercise to exhaustion tweaked over half the 18,000 molecules they tested in healthy middle-aged people, people with ME/CFS probably wouldn’t be surprised at all.

Plus, it intuitively makes sense. It’s only recently that almost everybody engaged in some sort of exercise regularly. Two hundred years ago, ninety percent of Americans lived on farms. Exercise is a fundamental process for humans, and the most in-depth study yet of exercise’s impacts on the human body showed just how fundamental it is.

Molecular Choreography of Acute Exercise. Kevin Contrepois,1,2,12 Si Wu,1,12 Kegan J. Moneghetti,2,3,4,5,12 Daniel Hornburg,1,12 Sara Ahadi,1,13 Ming-Shian Tsai,1,13. Ahmed A. Metwally,1 Eric Wei,1 Brittany Lee-McMullen,1 Jeniffer V. Quijada,1 Songjie Chen,1 Jeffrey W. Christle,2,3,5 Mathew Ellenberger,1 Brunilda Balliu,6 Shalina Taylor,7 Matthew G. Durrant,1 David A. Knowles,1,8 Hani Choudhry,9 Melanie Ashland,1 Amir Bahmani,1 Brooke Enslen,1 Myriam Amsallem,2,3 Yukari Kobayashi,2,3 Monika Avina,1 Dalia Perelman,1 Sophia Miryam Schu¨ ssler-Fiorenza Rose,1 Wenyu Zhou,1 Euan A. Ashley,1,3,10 Stephen B. Montgomery,1,6 Hassan Chaib,1 Francois Haddad,2,3,11,* and Michael P. Snyder1,2,11,14,* Cell. Volume 181, Issue 5, 28 May 2020, Pages 1112-1130.e16

“Everybody knows exercise is good for you, but we really don’t know what drives that at a molecular level, Our goal at the outset was to conduct a highly comprehensive analysis of what’s happening in the body just after exercising.” Michael Snyder

If you want to know what’s wrong – you have to know what right looks like. This and the studies coming out of the NIH’s $170 million Molecular Transducers of Physical Activity Consortium (MoTrPAC) are aiming to learn what healthy exercise looks like in the body. Their goal is to “develop a comprehensive map of the molecular changes that arise with physical activity” (Note – physical activity, not necessarily exercise).

The $170 Million NIH Exercise Study – and What it Could Do for ME/CFS

This study sure looked like it was part of the Consortium – and Mike Snyder’s Genomic Center at Stanford is part of the Consortium – but it wasn’t. All the funding for this particular study came from elsewhere. It’s no surprise, though, that it came out of the Snyder lab which, back in 2012, in what was hailed as a landmark paper, carried out the first deep longitudinal profiling ever done using multi-‘omics technologies (genomics, transcriptomics, proteomics, metabolomics, etc.) that was able to predict disease risk and onset.

That big NIH exercise project that recently got underway is going to include 2,700 people. This study had 38 people – but even so it produced some fascinating, and if they are validated, potentially novel insights that could benefit ME/CFS/FM.

Michael Snyder PhD and what looked to be a good proportion of the Stanford faculty, put  the 38 middle-aged healthy controls on a bike, exercised them to exhaustion and examined their blood before, and 2 min, 15 min, 30 min, and 1 h after exercise. They assessed seemingly every “ome” they could: their metabolome, lipidome, immunome, proteome, and transcriptome.

Results

Four clusters

Four clusters of molecular events were found.

The study identified four different clusters of molecules that occurred over the hour blood was taken. Note that each of these clusters are involved in different themes. They present a kind of  molecular “choreography” that needs to take place in order for exercise to work. Throw one or more of these clusters off and maybe you have ME/CFS. For the present, this study and others (Dr. Klimas has found clusters of activity as well), are identifying components of the exercise process that could conceivably be checked out in ME/CFS:

  • A cluster of inflammatory/oxidative stress molecules which ramped up immediately during exercise and then settled down. One of these involved a “fitness inflammatory signature”; i.e. a burst of inflammatory cytokines fifteen minutes after exercise which proved beneficial. The signature was centered on the IL-1b cytokine and potentially regulated by IL-5 and TGF-b.
  • A cluster of molecules centered on metabolic hormones (leptin, ghrelin) which decreased immediately and then returned to baseline within an hour.
  •  A cluster of molecules involving carbohydrate metabolism (cortisol/glucose) which showed up later and was deemed essential in replenishing energy stores. At 2 minutes, the body was metabolizing amino acids for energy, but then it switched to metabolizing glucose, a type of sugar, at around 15 minutes.
  • A cluster of molecules which involved amino acids which were metabolized to assist in muscle repair. This cluster was not replenished by the end of the testing period I hour after exercise.

Interestingly, the general sequence of molecular changes – an immediate explosion of inflammation and oxidative stress, followed later by a hormonal response (steroid hormones, corticosteroids) – was similar to that reported by Dr. Klimas in ME/CFS. (Dr. Klimas also reported autonomic nervous system changes).

Other interesting findings included the following:

  • A substance called myeloperoxidase (MPO). Secreted by neutrophils and a marker of oxidative stress, it turned out to be an important bridge to other pro-inflammatory and growth and protective factors.
  • Other processes identified included muscle repair, nitric oxide signaling in blood vessels, a decrease in mTOR signaling.
  • The authors suggested that an increase in ketone bodies later may have provided an additional energy substrate.
  • The production of long-chain polyunsaturated fatty acids that increased immediately post-exercise drew interest: did they reflect inflammation?
  • The two most significant pathways associated with peak VO2 (calpain and integrin pathways) are both involved in muscle regulation.

Somewhere in these key factors identified in healthy controls may lie the answer to ME/CFS. Something, after all, has gone wrong. So long as this and future studies identify what must go right for healthful exercise, we should be able to figure out what’s gone wrong.

Do the metabolic hormones that replenish energy stores not kick in? Is cortisol not elevated enough? Or do nitric oxide levels not increase enough to open the blood vessels? Or are the muscles not being repaired? Is our “fitness inflammatory signature” missing? Is the liver not producing enough ketone bodies?

Predicting Fitness er … VO2 Max with a Blood Test?

“It gave us the idea that we could develop a test to predict someone’s level of fitness,” Kévin Contrepois (1st author of study).

The most immediately important finding from the study, though, may be that the study found molecules in the pre-exercise period which predicted levels of VO2 max and ventilatory efficiency. Finding factors during rest which track VO2 max levels (a measure of energy production) could be groundbreaking for ME/CFS.

Think of the possibilities. A blood test which validated an inability to exercise? A diagnostic test for ME/CFS? Time will tell.

The study found a kind of poor VO2 max signature in the blood. While 1,000’s of molecules were involved, the main factor that popped out – leptin – has been associated with ME/CFS before. Younger’s longitudinal study pinpointed leptin as a possible factor driving the immune changes in ME/CFS, and higher leptin levels have been associated with pain in fibromyalgia. Snyder’s study found that higher leptin levels were associated with lower VO2 max in the healthy controls.

Getting “Younger”: Leptin, Chronic Fatigue Syndrome and Fibromyalgia

Two other fatty acids – triglycerides (TAG) and BCAA were also associated with lower peak VO2. Reduced levels of BCAA, have been found in ME/CFS before.  BCAA’s have been used in athletes to increase endurance but can also inhibit tryptophan entry into the brain.

On the other hand, other factors such as the transporter of thyroxine and retinol transthyretin (thyroid, hydroxy-fatty acids, corticosterone, hippuric acid, and bile pigments (i.e., biliverdin and bilirubin) were all positively associated with peak VO2; i.e. higher levels of each of these were associated with higher VO2 max. (Are some of these low in ME/CFS?).

One of them, hippuric acid, interestingly, is associated with microbial or gut diversity – which has found to be low in ME/CFS. The thyroxine transporter could fit in with the thyroid issues in ME/CFS.

The Atypical Thyroid Issues in Chronic Fatigue Syndrome (ME/CFS), Plus a New Thyroid Subset?

The Gist

  • This is the first of what will presumably be many studies to come which will provide many new insights into how exercise affects the body – a key concern of people with ME/CFS, in particular – given their post-exertional malaise problems.
  • The small, but intense, study involving 38 middle-aged healthy controls, came out of Michael Snyder’s lab at Stanford. Snyder is also part of the $120 million NIH study seeking to understand how exercise affects the physiology of the body at the deepest levels.
  • The study had the healthy controls exercise to exhaustion and then tracked how their different “omes” (genome, proteome, lipome, transcriptome) responded over the next hour.
  • To the researchers’ surprise, a single bout of exercise affected the levels of over half of the 18,000 molecules tracked.
  • The study uncovered four clusters of molecular events involving inflammation/oxidative stress, hormonal signaling, and carbohydrate and amino acid metabolism.
  • A signature in the blood that occurred prior to the exercise predicted how aerobically fit the participants were.  Such a test, if developed for ME/CFS, could conceivably be used as a diagnostic test.
  • Many other findings involving inflammation, hormones, oxidative stress, nitric oxide, muscle repair, etc. could provide a kind of roadmap for future investigations involving ME/CFS.
  • Next will come larger studies out of the 2,300-person NIH initiative focused at getting at the molecular roots of exercise in healthy people. Those studies should provide us with plenty of new insights into exercise that we can use to better understand ME/CFS and FM.

 

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The Stanford team is developing an algorithm to select a small number of molecules that are highly correlated with peak VO2; i.e. aerobic fitness. Expect to see that test in the future.

If an aerobic fitness signature can be found in the blood of healthy people my guess is that it should be much easier to find in the blood of exertion challenged people.

It’s possible that because this study was done in healthy controls, the results do not reflect what’s happening in people with ME/CFS. Our reason for reduced VO2 max may be different from theirs, but the fact that these researchers were able to uncover factors present at baseline that predict how much energy one can produce during exertion provides a lot of hope that the same could be done in ME/CFS.

Validation?

Maybe findings like this will also will help more people get it about “chronic fatigue syndrome”.  If a single bout of exercise affects that much of the body, then breaking that system should cause some real damage. Overloading a broken system like that by exercising should result some pretty stunning biological changes.

Dr. Klimas – who has already done similar gene expression and immune testing in ME/CFS and GWI – is, no doubt, lying in wait, waiting for this data to come out. Her studies haven’t been as comprehensive, but they do indicate that exercise causes higher amounts of inflammation, oxidative stress, autonomic nervous system and hormonal shifts in ME/CFS patients vs healthy controls.

A big question facing these huge omics studies is when they will produce tangible, actionable results. They’re very good at spitting out interesting masses of data. Translating that data into concrete treatment approaches hasn’t been so forthcoming.

Because Dr. Klimas has embedded her exercise/omics results into a computer model, her approach has resulted in concrete results: clinical trials in GWI and ME/CFS.  We don’t know if the very, very complex process she’s engaged in has worked – time will tell with that – but her work does indicate that big data studies can produce on-the-ground, tangible results.

The Future

As more studies like Snyder’s get done – and we get a better understanding of what exercise in a healthy person looks like – we should be able to show just how messed up the process is in ME/CFS. That should help researchers like Nancy Klimas, David Systrom, the folks at Workwell, Betsy Keller and others focused on exercise get funding for more intensive ME/CFS exercise studies.  If a single bout of exercise affected the levels of over half the molecules tested in this study, one wonders how many molecules a two-day exercise test would alter in ME/CFS.

This study is just the beginning of the in-depth molecular explorations of exercise we’re going to see happen over the next couple of years. If this is what we get out of one 38-person deep dive into exercise, the future may be bright.

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