“Tying up” or “Monday morning disease” is an old name to explain the phenomenon of horses getting painful muscle cramps, often on a Monday after a weekend off.
Tying up, or more properly exertional rhabdomyolysis, is extremely painful. The horses will be stiff and possibly struggle to move. They may also show dark urine (called myoglobinuria) if the muscle damage is severe enough that myoglobin, an abundant and critical protein in muscle, is visible in the urine. You can see more information about the symptoms of muscle disease, including tying up, at the University of Minnesota website.
While several different diseases can cause tying up, one of the common ones is “type 1 polysaccharide storage myopathy” or PSSM1. The Monday-ness was because PSSM1 horses do best when kept in regular work, even if it’s light. Time off actually increases their chances of tying up. PSSM1 is fairly common in stock horse breeds (quarter horses, paints, and appaloosas) as well as draft horses like Belgians and Percherons (see here).
This is a topic I know well. I started my career in Dr. Valberg’s Equine Neuromuscular Diagnostic Laboratory as a lab tech. Consequently, many of the papers I reference below are by old co-workers, mentors, and acquaintances.
The disease: Polysaccharide storage myopathy
But what, exactly, causes PSSM1?
Well, researchers have a few ideas and put some of that information right in the name: polysaccharide storage myopathy. It’s a muscle (myo-) disease (-pathy) where complex sugars (poly- for multipart -saccharides for sugars) are stored strangely. You might also notice that myo- has shown up in rhabdoMYOlysis and MYOglobin as well. Myoglobin is a protein that uses iron to store oxygen, it’s very similar to the hemoglobin protein found in red blood cells.
Anyway, sugar storage in the muscles of horses with PSSM1 is very strange. When you stain a muscle biopsy with a Periodic acid–Schiff (PAS) stain, which highlights sugars, visible clumps of sugar are visible. And these clumps are even resistant to amylase, an enzyme we have in our mouths that breaks down polysaccharides! You can see examples in this paper about PSSM1 which has an example in Figure 2.
Research revealed that horses with PSSM1 have what’s called a “gain of function mutation” in glycogen synthase 1 (GYS1) (the same paper as above). Gain of function is just the fancy way of saying the protein now does more of its usual function. Later work found it’s not just doing more, this crucial enzyme basically has a stuck gas pedal and cut brakes.
To be more precise, that research discovered that the mutated version of GYS1 was active even without its usual activator and that mechanisms that normally slow or stop its activity were clearly happening, but not affecting the rate at which the enzyme did its work.
But the next question was, why does this runaway enzyme cause such weird sugar storage and why does it hurt these horses?
Energy in muscle
To understand why this matters, we need a quick primer on energy flux in muscles. Muscles use up a LOT of energy and need to be able to access it quickly in the event of a sudden sprint. So, muscle cells favor storing energy as glycogen, which is quicker to access than fats. Muscle cells do keep some fats around, but they’re most useful for long-range exercise.
Glycogen is a big ol’ bush made of the sugar glucose. Specifically, branching chains of glucose attached to a protein center. Our friend glycogen synthase 1 (GYS1) is the enzyme that makes the long chains of glucose. Its name is descriptive too. Synthase. “-ase ” is the ending for enzyme names, and synthases are enzymes that synthesize things. Usually, the thing the enzyme makes or acts on is the first word in the name, glycogen in this case.
Other enzymes have jobs that free up the glucose from glycogen and start turning it into easier-to-use sources of energy.
The mechanism of PSSM1
So, why would having lots of glycogen make a horse tie up? Well, that part is where that same “later work” paper made some educated speculation. Remember how I said glycogen is like a bush? Well, GYS1 only makes long, singular chains. It needs a partner, a so-called glycogen branching enzyme, to make the branches. So, the researchers suspect that what’s happening in horses with PSSM1 is that the activity of the glycogen synthase is outstripping the activity of the branching enzyme, which is supposed to add a branch every few sugars. The researchers point to a similar glycogen storage disorder in mice that is caused by an unbalanced activity between GYS1 and glycogen branching enzyme. I also stumbled on a review paper that describes what happens when glycogen branching enzyme isn’t active and/or abundant enough.
Beyond that researchers only have educated guesses, or hypotheses, that still need to be tested. It’s possible that the abnormal glycogen yields less energy.
I found one study discussing a potential mechanism but couldn’t access the full article. From the abstract, it seems they found that horses with PSSM1 have reduced “OXPHOS”. OXPHOS, or oxidative phosphorylation, is what happens in your mitochondria to “make” energy. (I think OXPHOS is the coolest thing that happens in your body, but we don’t need to get into it here). I can’t fully tell from the abstract, but it seems the mitochondria were being fed their normal substrates (food), so this might be independent of the glycogen storage issues in horses with PSSM1. I’ll keep digging, but I’m on a (self-imposed) deadline to post this.
Final thoughts on tying up
So, to recap: some cases of recurrent tying up are horses with polysaccharide storage myopathy. Type 1 PSSM is caused by a runaway synthase in muscle that makes weird glumps of sugar, that may or may not yield enough energy when the horse tires to exercise. Researchers have made a lot of progress but there are still questions about how exactly the GYS1 mutation ends up causing muscle damage. Or why diet and exercise plans prescribed by vets manage the disease.
There are many more muscle diseases in horses and future posts will dig into some of them. I plan to talk about other types of exercise intolerance like ‘recurrent exertional rhabdomyolysis’, which occurs in thoroughbreds, and PSSM type 2, which affects Arabians and European Warmblood breeds.
But next week we’ll probably talk about Rolkur in dressage horses.
Disclaimer: I am not a veterinarian and this post is not medical advice. If you own a horse with any muscle disease,
you should seek out veterinary sources to learn more about how to best manage your horse’s care.