A new research publication in the respected journal Nature Communications (Appelman et al., "Muscle abnormalities worsen after postexertional malaise in long COVID", Nature Communications 15, Article number: 17 (2024)) describes an in-depth set of clinical studies that helps to explain a major long-term effect of COVID19 infection: Persistent muscular weakness, intolerance to exercise, and post-exercise malaise (tiredness and lack of energy). This study not only explains in granular detail the physiological changes many Long Covid sufferers experience, but also validates those sufferers’ experience, as many medical personnel — as well as friends and family — may not understand that what Long Covid sufferers are experiencing is real. The study was recognized by the FDA, and assigned Study Number NCT05225688. The study is observational, so no causality was determined, but what the researchers observed was very interesting and informative.
What Is Long Covid?
“Long Covid” is a catchall term that encompasses many different and seemingly unrelated symptoms:
Tiredness or fatigue that interferes with daily life; Symptoms that get worse after physical or mental effort (also known as “post-exertional malaise”); Fever; Difficulty breathing or shortness of breath; Cough; Chest pain; Fast-beating or pounding heart (also known as heart palpitations); Difficulty thinking or concentrating (sometimes referred to as “brain fog”); Headache; Sleep problems; Dizziness when you stand up (lightheadedness); Pins-and-needles feelings; Change in smell or taste; Depression or anxiety; Diarrhea; Stomach pain; Joint or muscle pain; Rash; Changes in menstrual cycles… [reformatted from original]
Some of the most problematic — and hard for medical staff to appreciate — symptoms are the first listed: fatigue and malaise. Many are quick to ascibe such symptoms as ‘laziness” or ”just not wanting to work”.
How Was The Study Structured?
The researchers started with a group of 25 patients with long COVID, and 21 control patients. They
obtained blood and skeletal muscle biopsies before and after a maximal exercise test (basically, riding on a cycle ergometer) that was designed to bring about post-exercise fatigue and malaise. Symptoms of malaise included muscle pain, greater severity of fatigue, and (interestingly) cognitive symptoms up to 7 days after exercise. The control group consisted of age- and sex-matched controls who fully recovered from mild SARS-CoV-2 infection. Both groups were healthy and socially active prior initial Covid infection.
What Were The Main Results?
Maximal oxygen uptake, and power output, was consistently lower among long Covid patients that control patients. Maximal exertion was achieved for patients in both groups, so that was not a differentiating factor. As may have been expected, lung function among long Covid patients was reduced compared to controls, but not cardiovascular function. But this reduction in lung function alone did not explain the fatigue and post-exercise malaise.
Capillary (tiny blood vessel) density was about the same between both groups, which is consistent with the cardiovascular function results above. What the researchers found, however, was an increase in “high-fatigable glycolytic fibers and lower mitochondrial function”.
So what are “high fatigable glycolytic fibers”? “Fatigable” just means “ susceptibility to fatigue; a tendency to get tired or lose strength”. “Glycolytic fibers” are a type of muscle fiber that primarily creates a molecule called ATP through anaerobic glycolysis rather than oixdative respiration. As a result, glycolytic fibers fatigue at a quicker rate. Let’s pause for a moment to dive into what this means.
A Bit About Energy Generation In Your Cells
ATP is shorthand for “adenosine triphosphate”. This molecule is ubiquitous in your body. Think of it as your cells’ “energy currency”. Each of your cells conducts tens of millions of chemical reactions every second, and most of those reactions need an energy source to take place. For most of those reactions, that energy source is ATP. Usually the energy is generated by pulling one of the phosphates off of ATP to create adenosne diphosphate (ADP), or occasionally two of the phosphates to create adenosine monophosphate (AMP). Without ATP, your cells become, energetically speaking, bankrupt.
Your cells generally use molecules of glucose, a 6-carbon sugar, to generate ATP. The glucose molecule is essentially a bank of energy stored in its ring structure and carbon-carbon bonds that your cells use to generate ATP. The first step is glycolysis (literally, the breaking apart of sugar). A molecule of glucose gets broken down into two molecules of what is called pyruvate. In the process, 2 ATPs are formed from ADP. Not a very efficient process, but the pyruvate is used in a subsequent set of reactions (called the Krebs Cycle) that is far more efficient — one cycle with both pyruvates generates an additional 34 molecules of ATP for a total of 36 per glucose molecule. (The actual biochemistry of ATP generation is a bit more complex, but this is sufficient for now.)
Where does ATP generation primarily take place in your cells? In small double-membrane organelles called mitochondria. The process of energy generation from glucose in mitochondria is called mitochondrial respiration. Clearly, then for normal energy levels, your body needs normally-functional mitochondria and a normally-functioning Krebs Cycle.
In Long Covid patients, however, that is not the case.
Back To The Research Results
The first really interesting result was that both the number of mitochondria, and overall mitochondrial respiration, were reduced in Long Covid patients vs. controls. Within muscle, most of the steps in the Krebs cycle showed reduced activity compared to controls. That is, overall energy generation (in the form of ATP) was significantly down in Long Covid patients after exercise, compared to controls. This goes a long way to explaining the fatigue that Long Covid patients feel. (Although not studied here, if the same effect is found in neurons, that may also explain the brain fog associated with Long Covid).
Long Covid patients’ muscle biopsies showed amyloid deposits around capillaries, but these deposits did not appear to interfere with capillary function.
So What Is The Takeaway?
It appears that post-exercise malaise in Long Covid is associated with a reduction in mitochondria, and mitochondrial function (which would lead to lower cellular energy production), and an increase in muscle damage post-exercise. It does not appear to be associated with a reduction in pulmonary function, amyloid deposits around muscular capillaries, or persistence of Covid19 virus in tissues.
This is a study that raises more questions than it answers — chiefly why these physiological and biochemical changes take place in Long Covid patients but not individuals who had Covid but apparently recovered to a healthy state. That research will likely be the route to developing therapies for Long Covid — and other disorders and conditions that resemble Long Covid (for example, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).