Understanding Polysaccharide Storage Myopathy Type 2 (PSSM2)

After more than two decades working alongside veterinarians to manage equine muscle disorders, I've witnessed the remarkable evolution of our understanding of Polysaccharide Storage Myopathy Type 2 (PSSM2). What began as a confusing collection of symptoms has transformed into a nuanced understanding of genetic variants, mitochondrial dysfunction, and epigenetic influences that shape how these conditions manifest in our horses.

Defining PSSM2 and Current Understanding

Unlike PSSM1, which has a clearly defined genetic mutation in the glycogen synthase 1 (GYS1) gene, PSSM2 represents a heterogeneous group of muscle disorders that share similar clinical presentations but lack the GYS1 mutation. The terminology has evolved as our understanding has deepened, with many researchers now referring to these conditions as Muscle Integrity Myopathy (MIM) to more accurately reflect the underlying pathophysiology.

The Current Genetic Variants

Genetic research has identified several variants that may contribute to muscle dysfunction in horses previously diagnosed with PSSM2. Currently, six semi-dominant gene variants (P2, P3, P4, P8, Px and K1) are being investigated as risk factors for the occurrence of Muscle Integrity Myopathy symptoms, with variants P5 and P6 also being discussed as alleles of the same gene (still unknown).

P2 Variant (MYOT gene - Myotilin) The P2 variant affects a gene that makes myotilin, a protein that works like the "glue" holding your horse's muscle together. Think of muscle fibers like a house being built—you need strong framing to keep everything in place while the workers do their job.

Myotilin is like the construction foreman who makes sure all the framing is solid, and the workers are organized. In a healthy muscle, this "foreman" keeps all the muscle parts connected tightly so they can work together to create smooth, powerful movement—like a construction crew working together to lift a heavy beam.

But in horses with the P2 variant, this foreman isn't doing his job properly. The "glue" becomes weak and unreliable, so the muscle's framing gets shaky. When your horse tries to exercise, the muscle can't hold itself together properly under stress. It's like trying to build a house with wobbly framing—things start falling apart or collapse all together.

This is why horses with P2 often show muscle stiffness, poor performance, and seem to struggle with exercise that should be easy for them. Their muscles are literally having trouble staying organized and working efficiently.

P3 Variant (FLNC gene - Filamin C) The P3 variant affects a protein called Filamin C, which works like the cables on a suspension bridge. If you've ever seen the Golden Gate Bridge, you know those cables are what keep the whole bridge stable.

In your horse's muscles, Filamin C acts like those critical cables, connecting different parts of the muscle and making sure forces are distributed evenly when the muscle contracts. These protein "cables" are flexible but strong, allowing the muscle to move smoothly while keeping everything properly connected.

With the P3 variant though, it's like some of the main cables on the bridge have broken. The muscle might still work, but it becomes unstable and can't handle normal exercise loads safely. Even having one bad copy of this gene can cause problems—that's what makes this variant particularly troublesome.

When these protein cables fail, your horse's muscle fibers can't contract efficiently and may get damaged during normal exercise. In humans, similar problems with this protein cause serious muscle diseases that can even affect the heart and breathing muscles, showing just how important these connections are. (Remember that organs are made up of muscle tissue too.)

P4 Variant (MYOZ3 gene - Myozenin 3) The P4 variant affects a protein that works like an air traffic controller in your horse's muscle. Imagine the muscle as a busy airport where lots of different systems need to communicate and coordinate perfectly to keep everything running smoothly.

Myozenin 3 is like the communication director who helps all the different "controllers" talk to each other. It's especially important for working with a protein called Calcineurin, which acts like the muscle's personal trainer—telling the muscle "you need to get stronger" or "you need to adapt to this new type of work."

When the P4 variant disrupts this communication system, it's like having radio static in the airport control tower. All the individual systems can still work, but they can't coordinate properly. The muscle loses its ability to organize itself and respond correctly to training.

Interestingly, humans don't seem to develop symptoms from similar mutations in this gene, but horses do. This might be because horses are such athletic animals that they need much better muscle coordination than most humans do in daily life. The result is horses that may look fine when resting but struggle to perform when asked to work.

P8 Variant (PYROXD1 gene) The P8 variant affects an enzyme that works like your horse's cellular "cleanup crew." Think of this enzyme as a specialized team that goes around the muscle cells with little vacuum cleaners, sucking up harmful debris (called free radicals) before it can damage the muscle.

In horses with the P8 variant, this cleanup crew isn't working properly—it's like having a broken vacuum cleaner. The muscle cells start to "rust from the inside out" because all the harmful stuff isn't getting cleaned up. This is why horses with P8 often show dramatic improvement when given extra antioxidants like vitamin E and C—these supplements basically provide extra cleanup crews to do the job the broken system can't handle.

You might notice that horses with P8 struggle more in cold, wet weather or during stressful times. This is because these conditions create even more "rust" or debris in the muscles, overwhelming an already broken cleanup system. It's like having a dirty house and a broken vacuum, then having a dust storm come through—things get bad quickly.

Px Variant (CACNA2D3 gene) The Px variant affects your horse's muscle "ignition system." Think of muscle contraction like starting a car—your horse's brain sends a signal (like turning the key), and this triggers the muscle to contract (like the engine starting). But there's more to this process than just an on/off switch.

In a normal horse, this ignition system works like a well-tuned car. When your horse's brain says "move," the signal travels down the nerves like electricity through wires, and when it reaches the muscle, it triggers the release of calcium—which is like the spark that actually starts the muscle contraction. The whole process is smooth, predictable, and perfectly calibrated.

Here's where it gets really interesting with the Px variant. Calcium in muscle cells works like water pressure in your house's plumbing system. When you turn on a faucet (the brain signal), you want just the right amount of water pressure—not a trickle that barely works, and not a blast that breaks the pipes.

In healthy muscles, calcium is stored in special compartments (like water tanks) and released in precise amounts when needed. The muscle uses this calcium to contract, then quickly pumps it back into storage so the muscle can relax. It's a perfectly balanced system of release, use, and cleanup.

But horses with the Px variant have faulty "pressure regulators" in their calcium system. Sometimes the calcium floods out like a burst pipe, sometimes it barely trickles, and sometimes the cleanup crew can't pump it back into storage fast enough. This means muscles might contract too hard, too weakly, or stay partially contracted when they should be relaxing.

The Px variant messes up the muscle's ignition control system, but in a very unusual way. Interestingly, it doesn't actually change the protein parts themselves—it's more like having the same car parts but with faulty wiring that affects how the instructions are read and carried out. Think of it like having a car manual that's been photocopied so many times that some of the words are blurry—the information is still there, but it gets misinterpreted.

This faulty "wiring" makes the muscle's calcium channels (the spark system) hypersensitive and unpredictable. Instead of releasing just the right amount of calcium when needed, these muscles might release too much, too little, or at the wrong times. It's like having a car where sometimes the engine barely starts, sometimes it revs wildly, and sometimes it backfires—all from the same gentle turn of the key.

This calcium chaos is why horses with Px often feel "tight" or "braced" even when they should be relaxed. Their muscles can't properly turn off because the calcium cleanup system isn't working correctly. It's like having faucets in your house that either won't turn on or won't turn off completely—you're always dealing with either no water or a constant drip.

This creates muscles that are "jumpy" and overreact to signals. That's why horses with Px are often very excitable, nervous, and reactive to their environment. Their muscles are constantly getting mixed signals or overreacting to normal stimuli—like having a car with a hypersensitive gas pedal that revs the engine with the tiniest touch. You might notice your Px horse jumping at shadows, being extra spooky on windy days, or seeming tense and "on edge" even in familiar situations.

The unpredictable muscle responses can also make these horses feel uncomfortable in their own bodies. Imagine if every time you tried to take a normal step, your leg muscles might respond with too much force (making you overstep) or too little force (making you stumble). This constant uncertainty about how their muscles will respond can make horses anxious and reactive as they try to compensate for their unreliable muscle control.

What makes Px particularly problematic is that it acts like an "amplifier" for other muscle problems. If your horse also has P2, P3, or P4 variants affecting the muscle structure, the Px variant makes those problems worse by forcing the already-damaged muscles to work harder and less efficiently. It's like having both a damaged engine AND a faulty ignition system—each problem makes the other one worse.

For example, if your horse has the P2 variant (weak muscle scaffolding) plus Px, not only are their muscles structurally unstable, but they're also getting erratic signals about when and how hard to contract. The poor muscle is trying to do its job with broken scaffolding while receiving confused instructions—a recipe for frustration and failure.

This amplifying effect explains why horses with multiple variants often show more severe symptoms than you might expect from adding the individual problems together. The Px variant doesn't just add its own problems to the mix—it multiplies the difficulties caused by other variants, creating a cascade of muscle dysfunction that can be particularly challenging to manage.

K1 Variant (COL6A3 gene) The K1 variant is different from all the others because it affects the "wrapper" around each muscle fiber, rather than the internal machinery. Think of this like the insulation around electrical wires—it protects and supports each individual muscle fiber.

This protective wrapper (called collagen type 6) is like a custom-fitted jacket for each muscle fiber. It provides structural support, helps the fiber keep its shape during contraction, and creates pathways for nutrients and oxygen to reach the muscle.

The K1 variant disrupts one of the three "threads" that must be woven together to make this protective jacket. It's like trying to make a strong rope but having one of your three strands be defective—the whole rope becomes weak and unreliable.

When muscle fibers lose their protective wrapping, they become more vulnerable to damage during normal exercise and have trouble maintaining their proper shape and function. In humans, similar problems cause serious muscle diseases with progressive weakness. While horses may not get as severely affected, they can still experience muscle weakness, exercise intolerance, and difficulty building or keeping muscle mass.

P5 and P6 Variants (Under Investigation) P5 and P6 are the newest mystery in the muscle puzzle. Scientists know these variants exist and can detect them, but they haven't figured out exactly which gene is involved or what protein it makes—it's like knowing there's a problem but not yet knowing exactly what's broken.

These variants are "recessive," which means they work differently than the others we've discussed. Think of genes like recipes—you get one recipe from your mom and one from your dad. With most of the other variants, having one bad recipe is enough to cause problems. But with P5 and P6, you usually need both recipe copies to be damaged before you see symptoms.

However, since P5 and P6 are two different damaged versions of the same mystery recipe, a horse could inherit P5 from one parent and P6 from the other. When this happens, the horse has two different damaged recipes but no good backup copy. Scientists are still figuring out whether these combinations will cause muscle problems.

The mystery around P5 and P6 shows how much we're still learning about muscle problems in horses. This is why some horses show symptoms even when they test negative for all the known variants—there are probably more genetic pieces to this puzzle that science hasn't discovered yet.

Myofibrillar Myopathy (MFM): A Distinct Clinical Entity

Research has identified that many horses previously diagnosed with PSSM2, particularly in Warmblood, Spanish, and Arabian breeds, actually suffer from Myofibrillar Myopathy (MFM). MFM is characterized by abnormal clumping of desmin protein in muscle fibers, where desmin accumulates in abnormal clumps around breaks in the alignment of contractile proteins. This represents a fundamentally different pathological process than traditional glycogen storage issues.

In MFM, there is structural damage to the muscle fibers caused at least in part by severely decreased antioxidant activity. This damage allows glycogen to pool between damaged fibers leading to the PSSM2 diagnosis. The distinction is crucial because MFM requires different management approaches than traditional PSSM2. For in-depth information about MFM, see our previous post here: Myofibrillar Myopathy (MFM) in Horses: A Functional Nutrition Perspective

Understanding Genetic Testing Considerations

The genetic testing landscape for these conditions continues to evolve as research progresses. While commercial tests are available for the identified variants, the relationship between genetic markers and clinical disease expression remains complex and is still being studied.

Current research indicates that these genetic variants may function as risk factors rather than direct causative agents, requiring specific environmental and nutritional triggers to manifest as clinical disease. This polygenic and multifactorial nature means that genetic testing provides valuable information about predisposition while emphasizing the importance of comprehensive management approaches.

The Mitochondrial Connection: When Cellular Powerhouses Fail

From a functional nutrition perspective, mitochondrial dysfunction plays a central role in PSSM2 and MFM pathophysiology. Mitochondrial respiratory capacity was severely decreased up to 49% in affected horses, with severe impairment in muscle mitochondrial respiration contributing to clinical symptoms.

Mitochondrial Exhaustion in PSSM2

Research in equine muscle disorders has identified several key aspects of mitochondrial dysfunction:

1. Reduced oxidative enzyme activity: Training enhances mitochondrial density with intense activity of oxidative enzymes, but affected horses show compromised function

2. Impaired fatty acid oxidation: Decreased ability to utilize fat as an energy source during exercise

3. Increased oxidative stress: Overwhelming of cellular antioxidant systems, particularly evident in horses with the P8 variant

4. ATP production deficits: Inadequate energy production for normal muscle function

The P8 Variant and Cellular Antioxidant Systems

The P8 variant affects the antioxidant system of the muscle, making antioxidants such as vitamin E and C especially important for horses with P8, but also supportive for horses with other genetic variants. This variant specifically compromises the cellular machinery responsible for neutralizing harmful free radicals produced during exercise.

How Your Horse's Environment Can Change How Their Genes Work

One of the most fascinating things about PSSM2 and muscle problems is that your horse's environment and training can change how their genes work—without changing the genes themselves. It's like having a dimmer switch on a light bulb: the bulb is the same, but you can make it brighter or dimmer depending on what you need.

Scientists call this "epigenetics," which is basically your horse's body putting little "sticky notes" on genes to tell them whether to work harder, work less, or work differently. Think of genes like a massive instruction manual for building and maintaining your horse's body. Epigenetics is like having someone go through that manual with a highlighter, marking some instructions as "very important—do this a lot" and others as "not so important right now—do this less."

How Exercise Changes Your Horse's Genetic "Settings"

When your horse exercises regularly, their body literally rewrites some of the "sticky notes" on their genes. Long-term, consistent training tells the muscle genes, "Hey, we're doing a lot of work here, so you need to get better at making energy and building muscle proteins."

Here's what's really amazing: when your horse gets fit, takes a break from training, and then starts training again, their muscles "remember" the previous training. It's like their genes keep some of the old "sticky notes" that say, "We've done this before—we know how to get fit quickly." This is why a horse that was once fit often gets back into shape faster than a horse that has never been fit before.

This "muscle memory" happens because exercise changes which genes are turned up or down, and some of these changes stick around even during rest periods. When training resumes, the muscles can quickly flip those genetic switches back to "athletic mode."

Key epigenetic mechanisms in PSSM2 include:

1. DNA methylation changes: Exercise alters methylation patterns of genes involved in energy metabolism

2. Histone modifications: Training affects chromatin structure and gene accessibility

3. MicroRNA regulation: Small RNA molecules that fine-tune gene expression post-transcriptionally

Environmental Triggers and Gene Expression

Clinical experience shows that PSSM2 symptoms often emerge or worsen following specific triggers:

• Prolonged rest periods

• Dietary changes

• Stress (transport, illness, vaccination)

• Seasonal variations

• Age-related changes

These triggers likely affect epigenetic regulation of muscle metabolism genes, explaining the variable nature of disease expression even within genetically predisposed individuals.

Functional Nutrition: Supporting Cellular Health at the Molecular Level

Effective management of PSSM2 and MFM requires understanding how nutritional interventions support cellular function at the mitochondrial level. Diet and exercise recommendations ideal for PSSM1 improve but do not eliminate the decline in performance and the “reluctance to go forward under saddle” characteristic of PSSM2, with 80% of owners reporting overall improvement.

Primary Nutritional Strategies

Substrate Modification for PSSM2 Cereal-free (grain free) and low-sugar feeding has become established in PSSM2, but is probably not absolutely necessary. However, supplements and feeds that are omega-3 rich are advisable. Unlike PSSM1, the strict carbohydrate restrictions may be less critical, but maintaining stable blood sugar levels and regulation remains beneficial.

Antioxidant Support Systems

PSSM horses should be fed vitamin E, however, the piece of this that frequently is missed is that regular Vitamin E AND Selenium testing should be performed to avoid creating a selenium deficiency. (Selenium is a co-factor to Vitamin E.) I recommend testing every 2 – 3 months.

Horses need a slightly increased supply of magnesium, sodium chloride (salt), as well as plenty of vitamin E (> 2,000 mg vitamin E per day). Trace elements such as zinc, manganese, copper and especially selenium should not be fed excessively, but to cover requirements.

Mitochondrial Support Protocols

Acetyl-L-carnitine supplementation redirects glucose away from glycogen storage and into energy pathways while supporting mitochondrial biogenesis and providing fuel for more efficient aerobic metabolism.

CoQ10 supplementation has been recommended for managing myopathies in several species due to its role in mitochondrial function and as an antioxidant. Horses with MFM have decreased expression of mitochondrial proteins and antioxidants in their muscle.

Advanced Functional Approaches -Targeted Micronutrient Support

• Selenium: Critical for antioxidant enzyme function, particularly glutathione peroxidase

• Magnesium: Essential for energy metabolism, muscle relaxation, and over 300 enzymatic reactions

• B-vitamins: Support mitochondrial function, particularly B1 (thiamine) for pyruvate metabolism

• Zinc and copper: Required for superoxide dismutase and other antioxidant enzyme systems

Anti-inflammatory Support

Omega-3 rich supplementation provides anti-inflammatory support and helps modulate inflammatory responses while supporting cellular membrane health.

Protein Quality Considerations

PSSM2/MFM horses lacking in muscle mass or strength benefit from branch-chain amino acid supplements, given within 45 minutes post-exercise. Select feeds with high quality protein content, containing high quality amino acids. Such as StableFeed’s Seasons Biome Blend.

Clinical Management: Integrating Science with Practice

Current diagnostic protocols recognize the complexity of these conditions:

1. Clinical presentation: Exercise intolerance, muscle stiffness, performance decline, behavioral changes

2. Muscle biopsy: Remains the gold standard, now including desmin staining to differentiate MFM

3. Genetic testing (often via hair): Provides information about predisposition and risk factors

4. Response to treatment: Improvement with appropriate management supports diagnosis

Treatment Protocols - PSSM2 Management

• Moderate carbohydrate restriction (less strict than PSSM1)

• Emphasis on antioxidant support

• Regular, consistent exercise with longer, slower warm-up periods

• Stress reduction strategies – including regular body work that consists of vagal nerve reset (osteopathy and carniosacrial)

PSSM2 and related muscle integrity myopathies represent a complex group of disorders requiring sophisticated understanding of cellular metabolism, genetic predisposition, and environmental modulation. The current genetic variants (P2, P3, P4, P8, Px, K1, and potentially P5/P6) provide valuable insights into disease risk, while the distinction between PSSM2 and MFM has important implications for management.

Success requires recognition that these are multifactorial conditions where genetic predisposition interacts with environmental factors, epigenetic modifications, and mitochondrial function to determine clinical outcomes. Functional nutrition approaches that support mitochondrial health, provide adequate antioxidant protection, and address individual metabolic needs offer the most promising strategies for improving quality of life and performance potential.

The key lies in understanding that genetic testing provides valuable information about predisposition while emphasizing that environmental management, nutrition, and exercise protocols remain the cornerstones of successful treatment. This integrated approach, combining genetic insights with proven management strategies, offers affected horses the best opportunity for comfortable, productive lives.

As our understanding continues to evolve, the focus should remain on supporting the fundamental cellular processes that determine muscle health, rather than seeking single genetic explanations for these complex, multifactorial conditions.

References

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