CORONAVIRUS PANDEMIC: EXERCISE BATTLING THE DEADLY CYTOKINE STORM

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On April 27, in my article entitled Coronavirus Pandemic: Diet and Nutrition – Battling the Deadly Cytokine Storm (musculardevelopment.com) I reported on the anti-inflammatory Mediterranean diet and how it may lower inflammation and tame down the cytokine storm. For many years, I was a member of the American Oil Chemical Society, an organization led by researchers from around the world studying the role of fats and oils in our diet. In the ‘80s early, epidemiology found that the “Greenland Eskimos who live on a traditional marine rich diet in long-chain omega-3 polyunsaturated fatty acids have a low incidents of cardiovascular disease and myocardial infarction (Nature, 1984).” Arachidonic acid is an inflammatory polyunsaturated fatty acid and is replaced in platelets and cell membranes with the anti-inflammatory omega-3 fatty acids from a high fish and fish oil diet. The high omega-3 fatty acid in the diet inhibited a clotting a prostaglandin called thromboxane A2 in blood platelets so they can’t aggregate and form dangerous clots. We also learned that high omega-3 fat diets also increased another prostaglandin in our vascular walls called prostaglandin I3 (PGI3) that increases vasodilation of blood vessels and improves blood flow in the body and to the heart. These were two mechanisms of action of the cardiovascular benefits of fish and omega-3 fatty acids in the Greenland Eskimo’s traditional diet and protected them from cardiovascular disease.

As you are aware from my past articles, I am a big advocate for the Mediterranean diet, low in saturated fats and rich in fish and omega-3 fatty acids. I recommended to Clint Eastwood to go on the Mediterranean diet over 25 years ago. He would often call me for advice on nutrition and diet recommendations. He valued how involved I was back then for staying on top of the latest scientific research. Clint is turning 90 years old this May and is one of the most health conscious individuals in terms of nutrition, training and fitness. I once went out to Burbank, CA to meet with Clint in his sound studios. He was working on the sound and finishing up for the launch of his new film at the time, Tightrope. While I was in the sound studio with him, he was pumping iron at the same time he was editing the film. He was amazingly fit and healthy back then and still today at 90 years of age!

A third mechanism of action of the omega-3 fatty acids and its inhibitory effect is a type of hormone-like compounds called leukotrienes. These leukotrienes are produced naturally from arachidonic acid, a polyunsaturated fatty acid found in animal fats in the diet. Arachidonic acid can increase inflammation and the inflammatory cascade, which can lead to the cytokine storm! Inflammation is linked to a higher risk of cardiovascular disease, cancer, metabolic syndrome and insulin resistance. Food sources of arachidonic acid include poultry such as duck, turkey and chicken, and beef, pork, butter, cream, and egg yolks. Duck and turkey are the richest food sources of arachidonic acid. Arachidonic acid is high in meat, poultry and eggs because of the feeding of corn (rich in linoleic acid, a polyunsaturated fat, abundant in vegetable oils) to cattle, hogs, and hens. Humans, unlike animals, do not convert linoleic acid found in whole grains or vegetable oils into arachidonic acid. Diets rich in polyunsaturated fats and monounsaturated fats are rich in virgin olive oil and omega-3 fats, which are found in fish in the Mediterranean diet. The Mediterranean diet lowers the body of arachidonic acid, the most inflammatory fatty acid and precursor that causes the inflammatory cascade and uncontrolled acute and chronic inflammation.

For many years, fitness enthusiasts and athletes have been gobbling up ibuprofen and other non-steroidal anti-inflammatory drugs to prevent pain and inflammation as a result of high-intensity workouts. In recent years, cox-2 non-steroidal anti-inflammatory drugs have been linked to serious cardiovascular accidents. It is now recommended that people with cardiovascular disease, or a high risk, not take non-steroidal anti-inflammatory drugs unless approved and recommended by their physicians or cardiologists.

Non-steroidal drugs such as cox-2 inhibitors are an effective analgesic and inhibit pain and inflammation by blocking prostaglandin E2 (PGE2), but they also block prostaglandin I2 (PGI2) prostacyclin that is the most important vasodilator formed in the endothelial of our vascular walls. This is one of the mechanisms through which non-steroidal anti-inflammatory drugs have adverse effects on the cardiovascular system in susceptible people.

 

EXERCISE, OVERTRAINING AND THE CYTOKINE STORM

Over the years, marathon races have become a popular trend. Training for marathons and running 26.2 miles has been shown to have a negative effect on the cardiovascular system. It has been shown to increase interleukin-6, inflammation, c-reactive protein in arteries and increase plaque buildup and calcium levels in our artery walls. High mileage and distant running can also lead to overtraining and elevated cortisol levels and lower immune function. More isn’t always better! Marathon runners are often overtrained and prone to immune suppression and chronic illness and colds. Marathons are physically very challenging and are extremely stressful for our bodies. To help prevent overtraining, we must have proper rest, sleep and nutrition for enhanced recovery and performance. Also, your physician can prescribe a blood test to measure your c-reactive protein (CRP), an indicator of systemic inflammation. Running is clearly good for your health, weight loss and cardiovascular system, but overtraining syndrome from excessive running can clearly be bad for your health and make you more susceptible to the coronavirus. 

WHAT ARE CYTOKINES? THE GOOD, THE BAD & THE UGLY

As I mentioned in my last article, people infected with the COVID-19 virus often develop a deranged, hyperimmune response in the lungs resulting in elevation of interleukin-6, inflammation, which can result in pneumonia, lung failure, respiratory collapse (requiring a possible ventilator), and/or death.

Interluekin-6 is also released during exercise and muscle contraction. Circulating levels of interleukin-6 are affected by duration of exercise and intensity. High levels of IL-6 can increase inflammation and low levels of IL-6 can work as an anti-inflammatory by stimulating AMPK. With exercise, circulating IL-6 can be elevated for several hours to several days. IL-6 levels in the blood normally peak immediately post-exercise and return to baseline levels by two days. Normally these cytokines such as IL-6 activate our immune response and certain white blood cells called macrophages that destroy and kill dangerous pathogens, bacteria and viruses. These white blood cells are like “killer, phagocytic Pac Men” that release reactive oxygen species (ROS) free radicals and kill these bacteria and viruses and at the same time, these ROS free radical species damage normal tissue, including muscle and can cause cell death.

At this time, several drugs are being investigated to help battle the cytokine storm in COVID-19 patients such as tocilizumab (Actemra) developed by the biotech company Genentech and sold by Roche Holding AG. Side effects of these anti-inflammatory drugs approved for rheumatoid arthritis include upper respiratory infections, hypertension, hepatotoxicity and increased risk of certain cancer by downregulating the immune system.

The Mediterranean diet, which I mentioned earlier in my article, has great potential to help naturally tame down the uncontrolled hyperimmune response from overtraining and the cytokine storm. The Mediterranean diet has been shown to lower inflammatory prostaglandins, leukotrienes and interleukin-6 in our tissue and muscle, and lower inflammation. It has also the healthiest diet based on the latest scientific research.

Unlike excessive long-distance running, it has become evident in the scientific literature that eccentric resistance weight training exercise does not normally increase interleukin-6 in the blood! Like I said earlier, exercise duration is the single most important factor determining post-exercise plasma IL-6. That’s why long hours of cardiovascular training such as training for a marathon can boost abnormal IL-6 levels, which can increase the risk of overtraining, immune suppression, loss of lean body mass and have a negative effect on your health. Research has shown that six minutes of rowing on an exercise ergometer can increase plasma IL-6 by two-fold. A 10-fold increase in plasma IL-6 requires exercise for 1.9 hours while a 100-fold increase of plasma IL-6 requires exercise lasting six hours – especially in response to running. Long-distance running has also been shown to lower the anabolic hormone testosterone and elevate interleukin-6, which can lower insulin-derived-growth-factor (IGF-1) and raise myostatin, a catabolic myokine. High levels of myostatin can enhance muscle loss and inhibit muscle growth. Creatine, as a dietary supplement, has been shown to lower myostatin in muscle and increase lean body mass and performance. Post-workout nutrition is very important to help recover from long-duration and high-intensity workouts and combat high levels of interleukin-6. Adequate carbohydrate and protein in the diet are essential as part of a post-workout meal. Carbohydrate and the essential amino acid leucine have been shown to lower interleukin-6 levels.

A study in the journal SL Nutrition and Metabolism on September 5, 2017 reported that, “results demonstrate that free-leucine supplementation, but not within a mixture of BCAA can influence serum cytokine pattern in order to promote a more anti-inflammatory pattern in healthy humans.” Leucine is a potent activator of muscle protein synthesis in muscle. Five grams of pure leucine post-workout can be taken on an empty stomach along with creatine before a post-workout recovery meal, rich in complex carbohydrates and protein containing all the essential amino acids for protein synthesis recovery and muscle repair and growth. Like I said earlier, marathon running dramatically raises interleukin-6 in the body and can have a hyperimmune response, resulting in the cytokine storm, especially if you train daily of long duration.

On March 11, 2020 the health news website STAT published the story and reported in The Wall Street Journal (Thursday, April 30, 2020) about a “A 47-year old New Jersey doctor who caught COVID and declined from a marathon’s runner’s health to near death in days. A physician friend, and infectious-disease specialist, did try hydroxychloroquine with Zithromax … it didn’t help! After more back-of-the-envelope analysis, she tried the tocilizumab, an anti-inflammatory drug approved for rheumatoid arthritis. His fever of nearly 104 receded and his oxygen levels became normal. Does this prove the arthritis drug for COVID-19? Who knows? It looks as if it worked in this corner of the battlefield and by the way, it saved another young doctor in Seattle who had COVID.”

 

Sources:

1. Centers for Disease Control and Prevention (CDC)
2. National Institutes of Health (NIH)
3. Johns Hopkins Center for Health Security
4. Food & Drug Administration (FDA)
5. Journal of American Medical Association (JAMA)
6. New England Journal of Medicine (NEJM)

 

References:

1. The spread of Covid-19 and the Boston Marathon: We can run another day. Elizabeth Cooney March 11, 2020. STAT News https://ift.tt/38Ls4hY
2. The Wall Street Journal; Thursday, April 30, 2020 by Daniel Heenegar.
3. Carson JA, Baltgalvis KA. Interleukin 6 as a key regulator of muscle mass during cachexia. Exerc Sport Sci Rev 2010;38(4):168‐176. doi:10.1097/JES.0b013e3181f44f11
4. Belizário JE, Fontes-Oliveira CC, Borges JP, Kashiabara JA, Vannier E. Skeletal muscle wasting and renewal: a pivotal role of myokine IL-6. Springerplus. 2016;5:619. Published 2016 May 13. doi:10.1186/s40064-016-2197-2
5. Coronavirus Pandemic: Diet and Nutrition Battling the Deadly Cytokine Storm – The Latest Research! Steve Blechman. Advanced Molecular Labs. April 24, 2020 https://ift.tt/2C6dsPJ
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Pilot Study. Humberto Nicastro, Marcelo Carvalho et al. SL Nutrition and Metabolism. September 2017. https://ift.tt/3fkormU

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18. Obesity Exacerbates the Cytokine Storm Elicited by Francisella tularensis Infection of Females and Is Associated with Increased Mortality. Mireya G. Ramos Muniz et al. June 26, 2018. Journal of Bio Med Rsch. https://ift.tt/2Wyg8MF
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22. Mediterranean Diet Reduces Risk of Incident Stroke in a Population With Varying Cardiovascular Disease Risk Profiles. Paterson, K. E., Myint, P.K., Jennings, A., Bain, L., Lentjes, M., Khaw, K.T., & Welch, A.A. (Oct 2018). Stroke, 49 (10), 2415-2420. Advance online publication. doi:10.1161/STROKEAHA.117.020258
23. Marialaura Bonaccio, Augusto Di Castelnuovo, Simona Costanzo, Mariarosaria Persichillo, Amalia De Curtis, Chiara Cerletti, Maria Benedetta Donati, Giovanni de Gaetano, Licia Iacoviello. Interaction between Mediterranean diet and statins on mortality risk in patients with cardiovascular disease: Findings from the Moli-sani Study. International Journal of Cardiology, 2018; DOI: 10.1016/j.ijcard.2018.11.117
24. Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet. Iris Shai, R.D., Ph.D., Dan Schwarzfuchs, M.D., Yaakov Henkin, M.D., Danit R. Shahar, R.D., Ph.D., Shula Witkow, R.D., M.P.H., Ilana Greenberg, R.D., M.P.H., Rachel Golan, R.D., M.P.H., Drora Fraser, Ph.D., Arkady Bolotin, Ph.D., Hilel Vardi, M.Sc., Osnat Tangi-Rozental, B.A., Rachel Zuk-Ramot, R.N., et al., for the Dietary Intervention Randomized Controlled Trial (DIRECT) Group. July 17, 2008. N Engl J Med 2008; 359:229-241
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