Thread by @PutrinoLab

Time for a 🧵 about metabolically-led post-exertional symptoms. This is quite possibly the most dangerously misunderstood piece of #LongCovid, #MECFS and infection-associated chronic illness puzzle (including non-viral pathologies that involve mitochondrial damage). (1/n)

First: many things can cause post-exertional symptoms, especially in the case of #LongCovid, where a large % of people have associated #dysautonomia. Understanding this is crucial to maximizing the utility of interventions such as autonomic rehabilitation and pacing (2/n)

without doing more harm than good. However, today is about metabolically-driven #PEM/#PESE. It should be fairly well-established at this point that many people with conditions like #LongCOVID and #MECFS have evidence of mitochondrial dysfunction, oxidative stress and (3/n)

imbalances in lactic acid levels. In fact, these are some of the most robust examples in the literature of how people with these conditions differ from the general population. It can feel as though there is a bit of a “chicken and egg” dilemma when we try to conceptualize (4/n)

what came first: mitochondrial dysfunction or oxidative stress? Thanks to a piece by the always-brilliant @microbeminded2 and @MBVanElzakker, we have an answer infection-associated chronic illnesses ij.hapres.com/htmls/IJ_1341_…. In #MECFS and ME/CFS-like illnesses that are not (5/n)

virally-mediated it is a good chance that oxidative stress leads the cascade, but today is about #LongCOVID so let’s talk about the viral path. For those who don’t know, our cells use a very specific fuel source called ATP that is produced in a part of the cell called the (6/n)

mitochondria. Unfortunately, ATP also fuels the cellular activities of viruses. As such, as the @microbeminded2 piece elegantly explains, when a virus enters our cells it quickly hijacks our mitochondria to fuel viral replication and other viral activities. In other words (7/n)

when you are infected by a virus like #COVID19, you are infected by a little energy thief: taking your hard-earned ATP and using it for its own purposes. Not only does this mean that the virus is proliferating on stolen energy (rude!) but it also means that your cells must (8/n)

perform their regular functions with far less energy. So this is where things get cyclical: we have hijacked mitochondria resulting in inefficient, “stressed“ cells. Our cells are producing energy “for two” now, but barely managing to function, leading to the overproduction (9/n)

of reactive oxygen species (ROS), which we can think of as the “exhaust fumes” of our mitochondria. ROS are bad characters - systemically, they can trigger inflammation and (wait for it) hypocapnia (iopscience.iop.org/article/10.108…; h/t @wood_jamie_1, @LauraTabacof and @JoshDuntz). (10/n)

Unfortunately, once the body is experiencing oxidative stress, the mere act of producing more energy starts to damage the mitochondria. Thus, the unhappy cycle: Hijacked, limping mitochondria—>oxidative stress—>further mitochondrial damage—>further oxidative stress. —>… (11/n)

This grim cycle occurs at different levels of severity depending on individual physiology and shows us why, in some cases of #LongCOVID (and #MECFS), ALL forms of physical rehab (no exceptions) can be harmful, and though pacing can be a lifeline, it doesn’t halt functional (12/n)

decline. So where do we go from here? 1. We need better *mainstream* lab tests and encouragement of healthcare providers to perform routine testing for mitochondrial dysfunction, oxidative stress and lactic acid levels to identify those for whom physical rehab/exertion is (13/n)

*contraindicated*. 2. Better understanding that symptom triggers will depend on the types of cells that are affected: if your muscle cells are deeply affected, you’ll have lots of lactate buildup and terrible responses to physical exertion. However if cells in your GI tract(14/n)

are more affected, then digestion is now your “exertion” - you may be able to tolerate aerobic activity just fine, but consuming food that is hard to digest like a steak or high fiber meal will trigger your strongest symptoms. As such, diets like keto, whole30, vegan, etc (15/n)

will produce mixed results depending on how much work your body has to do to digest the food you choose. Everyone’s individual triggers must be identified and addressed. 3. Supplemental support for mitochondria *may* move the needle on symptoms and should be attempted (16/n)

under the supervision of a clinician: ask about things like Coq10 and nicotinamide riboside that can help to reduce/repair mitochondrial damage. However, we must also acknowledge that in cases where viral persistence is occurring, these supplements will only take us so far (17/n)

if we don’t have a way of clearing the virus (here’s hoping for some successful antiviral trials soon 🤞🏼), which also brings us along to point 4. None of these interventions are a “silver bullet” for all presentations of #LongCOVID. Just clearing virus won’t repair your (18/n)

mitochondria or resolve the dysautonomia or #MCAS that has developed due to chronic inflammation and/or autoimmune reactions. Just addressing mitochondrial dysfunction won’t clear persistent virus or solve your #PEM/#PESE because your cells are still hijacked. We have a (19/n)

LOT of basic discovery work left to do before we get a good handle on #LongCOVID, but in the meantime the worst thing we can do is not listen to one another, fail to read deeply and across disciplines and forget our knowledge of physiology in favor of snake-oil and the (20/n)

allure of miracle cures. One size will never fit all for this illness. I hope, above all, that this thread has helped to explain the physiology behind how exertion can be CATEGORICALLY harmful to many with #LongCOVID and #MECFS based upon what is happening in their cells 🙏🏻 (end)