Rhabdomyolysis is the breakdown of muscle tissue that releases damaging proteins into the bloodstream. Typically, it is a condition associated with extreme conditions, however, there is an exercise-induced form known as exertional rhabdomyolysis. 

This can affect anyone who trains hard. However, your genetics can significantly influence how susceptible you are. Several gene variants, including those affecting muscle structure, energy metabolism, and oxidative stress response, have been associated with increased rhabdomyolysis risk. 

Understanding your genetic profile won't limit you from training hard, but it can help you train smarter and recover safer.

Managing your training load is important for everyone, but for some of us, it can be an area we need to pay more attention to due to a risk of exertional rhabdomyolysis.

Your genes alongside exercise intensity, training history, hydration, ambient temperature, and certain medications (such as statins) are all independent risk factors of exertional rhabdomyolysis.
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What is rhabdomyolysis and why does it matter for athletes?

Rhabdomyolysis - often shortened to "rhabdo" - is a condition in which muscle fibres break down and release their contents, such as creatine kinase (CK) and myoglobin, into the bloodstream. The most concerning of these is myoglobin, an oxygen-carrying protein that, in large quantities, can block and damage the kidneys. In severe cases, this can progress to acute kidney injury.

For most people, rhabdomyolysis is associated with extreme circumstances: catastrophic trauma, severe heatstroke, or certain medications and toxins. But there is a well-documented exercise-induced form - exertional rhabdomyolysis - that can occur in otherwise healthy individuals following intense or unaccustomed physical activity. This is the form most relevant to athletes and active people, and it exists on a spectrum. At the milder end, individuals may experience only elevated levels of creatine kinase (CK) - an enzyme released from damaged muscle - in their blood, without any clinical symptoms. At the more severe end, muscle swelling, weakness, and the characteristic dark, cola-coloured urine that signals myoglobin in the bloodstream can all present.

Understanding rhabdomyolysis is not about alarming people away from hard training. It is about recognising that some individuals are biologically more vulnerable to this kind of muscle cell breakdown than others, and that your genetics are an essential part of understanding the whole picture.
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Which genetic variants are linked to rhabdomyolysis risk?

There have been two key papers that have studied the genetic differences in exertional rhabdomyolysis risk: Del Coso et al. (2017) in PLOS ONE and a subsequent analysis published in the Journal of Cellular Physiology. Some of the key SNPs these papers identified as being associated with rhabdomyolysis risk are ACE, ACTN3, CKMM, IGF2, IL6, MLCK, and TNFα:

• ACE (Insertion/Deletion polymorphism): The ACE gene encodes for angiotensin-converting enzyme, which regulates blood pressure and vascular tone through the renin-angiotensin system. Studies have found associations between the II genotype and higher CK response following eccentric exercise, but the findings have been mixed across different studies. 
• ACTN3 R577X (rs1815739): The XX genotype (no alpha-actinin-3) was associated with increased susceptibility. You can read more about the ACTN3 gene in our blog here.
• CKMM (NcoI — rs1803285): The CKMM gene encodes the muscle-specific isoform of creatine kinase, the enzyme responsible for regenerating ATP from phosphocreatine during high-intensity contractions. Variants of this gene have been associated with differences in both baseline CK levels and the magnitude of CK elevation following intense exercise.
• IGF2 (C13790G — rs3213221): The IGF2 gene encodes insulin-like growth factor 2, a hormone with important roles in muscle growth, repair, and the regulation of satellite cell activity. The GG genotype has been shown to experience greater force loss, soreness, and CK response than CC counterparts following eccentric exercise.
• IL6 (174G>C — rs1800795): The IL6 gene encodes interleukin-6, a cytokine involved in both the pro-inflammatory response to muscle damage and the regulation of satellite cell proliferation after intense exercise. The C allele has been associated with higher CK values following eccentric contractions. 
• MLCK (C37885A — rs28497577): The MLCK gene encodes myosin light chain kinase, an enzyme that phosphorylates the regulatory light chains of myosin, increasing the number of force-generating cross-bridges during contraction and influencing the mechanical strain placed on the muscle fibre. There is mixed evidence on this gene. One study found A-allele carriers had greater strength loss and elevated plasma CK following eccentric contractions, while another found CA heterozygotes had fewer signs of muscle damage than CC homozygotes.
• TNFα (308G>A — rs1800629): The TNFα gene encodes tumour necrosis factor alpha, a pro-inflammatory cytokine associated with the upregulation of catabolic pathways and suppression of protein synthesis in skeletal muscle. The GG genotype has been associated with higher CK values than GA heterozygotes following eccentric exercise. 
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How do these variants actually damage muscle?

Although these genetic variants influence different biological pathways, they all interact with the muscle cells in some form. 

The most direct structural contribution comes from ACTN3 and MLCK. Without functional alpha-actinin-3, the Z-disks that border each contractile unit are composed primarily of alpha-actinin-2, leaving the fibre less mechanically stable under the repeated high-force contractions of sustained endurance exercise. MLCK compounds this by influencing how hard the fibre contracts in the first place: enhanced regulatory light chain phosphorylation increases the number of force-generating cross-bridges, raising the mechanical strain placed on the membrane during each contraction cycle. A fibre that is both structurally less stable and contracting with greater internal force faces a meaningfully lower threshold before membrane integrity fails.

CKMM sits at the intersection of structural and energetic vulnerability. As the enzyme responsible for regenerating ATP from phosphocreatine during intense contractions, CK (creatine kinase) activity is central to maintaining the energy supply that powers the ionic pumps keeping calcium in check. Variants that affect the localisation, translation efficiency, or stability of the CKMM protein, such as the NcoI polymorphism, may subtly impair this process, reducing the cell's capacity to sustain energy balance under sustained exertional load.

IGF2 and ACE operate one step removed from the contractile event itself, shaping the muscle's broader capacity to tolerate and recover from damage. IGF-II influences satellite cell activation and differentiation - the repair mechanism that patches minor membrane disruption before it can accumulate. Variants associated with lower IGF-II signalling reduce that repair capacity, meaning damage that might otherwise be resolved quietly instead persists and progresses. ACE, through its role in vascular tone and blood flow to working muscle, affects how efficiently oxygen and substrate are delivered during exertion. Lower efficiency could lead to greater build up of muscle damage markers. 

Once membrane disruption begins - whether through structural fragility, mechanical overload, or energetic failure - IL6 and TNFα determine how aggressively the inflammatory cascade responds to it. Both genes are implicated in the pro-inflammatory environment that follows muscle damage: IL6 modulates the release of downstream cytokines including TNFα itself, while TNFα drives catabolic pathways and suppresses protein synthesis. In individuals with genotypes associated with a more pronounced response from either gene, the inflammatory reaction is amplified, accelerating the breakdown of muscle fibres and broadening the zone of injury beyond what the mechanical event alone would have caused.
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Does having one of these variants mean I'll get rhabdomyolysis?

Although these gene variants can impact on muscle damage risk in multiple ways, their individual effects are only significant when combined together - this is what the Del Coso study found. This finding reflects the biology accurately: it is the combination of multiple genetic vulnerabilities across multiple systems, under the sustained stress of an event like a marathon, that tips the balance from manageable muscle stress into the cell membrane failure and intramuscular protein leakage that defines exertional rhabdomyolysis.

It is also important to acknowledge the significant role environmental factors play on your risk of rhabdomyolysis. The temperature you are exercising in, your hydration status, the management and progression of your work load, certain medication, and lifestyle factors such as alcohol intake, will all contribute to the risk. But these are the areas in which you can take proactive action to minimise the risk of developing rhabdomyolysis. 
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FAQs

1. What are the warning signs of exertional rhabdomyolysis?

The typical symptoms to look out for are dark, cola-coloured urine, muscle swelling, severe muscle soreness that is disproportionate to effort (much greater than the usual DOMS you may experience!), and feeling weak. Symptoms would usually occur 12-36 hours following intense exercise. These are warning signs and if you experience any of these, it is important that you seek medical attention so a blood test can be taken to check your creatine kinase levels, and appropriate treatment can be implemented. Milder cases of rhabdomyolysis may only cause unusual fatigue.
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2. If I have the ACTN3 XX genotype, am I at higher risk?

The research around the XX genotype does show there is an increased risk of post-exercise muscle damage, including exertional rhabdomyolysis. This is likely due to the lack of alpha-actinin-3 production causing less stable muscle fibres, making them vulnerable to greater levels of damage following exercise. However, as mentioned, it is important to note that a single gene variant on its own will only have a very small impact on your risk.
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3. Does rhabdomyolysis risk vary by sport or exercise type?

Yes. Eccentric-heavy exercise (downhill running, plyometrics, heavy lifting), unaccustomed high volume, and exercise in the heat carry the highest risk. Genetic variants interact most strongly with these specific stressors, so training load management is especially important for higher-risk genotypes who participate in these types of activities or conditions.
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4. Can I train hard if I know I carry a risk variant?

Of course. Knowing your risk allows you to implement the right strategies to manage your training load and control environmental risk factors. Gradual progression, adequate hydration, avoiding NSAID use around intense sessions, and prioritising recovery all reduce risk while still allowing you to incorporate hard training sessions.
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5. Are there nutritional or supplemental strategies that are important for higher-risk individuals?

Your nutrition is a key way to ensure your body is adequately fueled and hydrated before, during and after exercise, which will help to reduce the risk of rhabdomyolysis. Hydration is a crucial component so ensuring you keep hydrated throughout your day, and particularly during and after exercise is important. Protein and omega-3 fatty acids are dietary components that will support reducing prolonged inflammation and aid muscle growth and repair. Tart cherries' antioxidant components have shown some promising positive effects on reducing muscle soreness and markers of muscle damage, so adding this either through a juice or supplement can be a great addition to your recovery strategies to help keep the risk of rhabdomyolysis low.
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6. Should I talk to a doctor about my genetic risk for rhabdomyolysis?

If you have a history of unusual post-exercise symptoms or have any concerns about your genetic result, discussing your result with a doctor or other medical professional can be useful. It may help guide some clinical decisions or appropriate triaging of other testing. We are partnered with Thrive Doctors - a team of experienced doctors who will discuss and help you understand what your result means for your health.
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7. Is rhabdomyolysis risk the same in men and women?

Most research on exertional rhabdomyolysis has been conducted in military populations that are predominantly male, which may limit generalisability to women. Hormonal differences (particularly oestrogen's potential role in membrane stabilisation) may modulate risk, but the evidence here remains limited.

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Author‍

Geraldine Campbell, MSc is an exercise physiologist who has worked at FitnessGenes for over 10 years. 

The work underpinning FitnessGenes' US patent (US 10,621,499 B1) covers methods for generating personalised training and nutrition recommendations from genetic data.

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References

Del Coso J, Valero M, Salinero JJ, Lara B, Gallo-Salazar C, et al. (2017) Optimum polygenic profile to resist exertional rhabdomyolysis during a marathon. PLOS ONE 12(3): e0172965. https://doi.org/10.1371/journal.pone.0172965

Williams, A.G. and Folland, J.P. (2008), Similarity of polygenic profiles limits the potential for elite human physical performance. The Journal of Physiology, 586: 113-121. https://doi.org/10.1113/jphysiol.2007.141887

Baumert, P., Cocks, M., Strauss, J. A., Shepherd, S. O., Drust, B., Lake, M. J., Stewart, C. E., & Erskine, R. M. (2022). Polygenic mechanisms underpinning the response to exercise-induced muscle damage in humans: In vivo and in vitro evidence. Journal of Cellular Physiology, 237, 2862–2876. https://doi.org/10.1002/jcp.30723

Del Coso, J., Valero, M., Salinero, J.J. et al. ACTN3 genotype influences exercise-induced muscle damage during a marathon competition. Eur J Appl Physiol 117, 409–416 (2017). https://doi.org/10.1007/s00421-017-3542-z

Yamin, C., Duarte, J.A.R., Oliveira, J.M.F. et al. IL6 (-174) and TNFA (-308) promoter polymorphisms are associated with systemic creatine kinase response to eccentric exercise. Eur J Appl Physiol 104, 579–586 (2008). https://doi.org/10.1007/s00421-008-0728-4

Daab, W., Bouzid, M.A., Nassis, G.P. et al. Effects of Tart Cherry Juice Supplementation on Recovery from Exercise-Induced Muscle Damage in Athletes: A Systematic Review and Meta-Analysis. Sports Med - Open 12, 40 (2026). https://doi.org/10.1186/s40798-026-00993-3