1.1 Introduction

At some point, most people have experienced a muscle cramp at one point or another, even the most fit athletes.^[1] Cramps are generally agreed upon to be any sudden and involuntary painful skeletal muscle contractions seemingly without warning or probable cause. It is found that cramps can become more frequent when someone has a neuromuscular disease or being dehydrated or excessive exercise.^[2] Even though the true source of cramps are still unknown, there are still ways that skeletal muscle cramps can be treated. This is what makes skeletal muscle cramps a phenom, and why there is constant research around it.

2.1 Skeletal Muscle Anatomy

Cramps are usually found most often in the triceps surae, hamstrings, and quadriceps^[3], however this does not stop them from being prevalent in other parts of the body. To first understand how cramps begin, it is best to understand some basic muscle anatomy. Firstly, skeletal muscle is made up of many fascicle groups which are surrounded by epimysium. Epimysium is a sheet of connective tissue which surrounds the muscle. Each fascicle contains some muscle fibres that are surrounded by perimysium. Perimysium is just a continuation of epimysium. Inside the muscle fibre is then myofibril, which contains the sarcomere, the main thing that causes contraction in the muscle. Sarcomeres contain two filaments, a thick filament (actin) and a thin filament (myosin).

2.2 Muscle Contractions

Skeletal muscle contraction is a complex physiological process. Firstly, the process begins with a signal travelling along a motor nerve to its endings on a muscle fibre. At each ending, the nerve secretes acetylcholine (ACh), which binds to receptors on the muscle fibre membrane, initiating a chemical reaction within the muscle fibre. The binding of ACh will then trigger the release of calcium ions from the sarcoplasmic reticulum. The released calcium ions bind to troponin, causing tropomyosin to move away from the myosin-binding sites on actin. The next step involves the formation of cross-bridges between myosin heads and actin, which lead to the power stroke. During which, the myosin heads pull the actin filaments towards the centre of the sarcomere. This process is fueled by adenosine triphosphate (ATP). As myosin heads pull on the actin filaments, the filaments slide past the myosin filaments within the muscle fibre, causing the sarcomere to shorten. The cross-bridge cycling continues if calcium ions remain in the sarcoplasm to bind to troponin, and ATP is available to drive the cycling process. This results in more muscle contraction until calcium ions are pumped back into the sarcoplasmic reticulum and tropomyosin recovers the myosin binding sites on actin, which leads to muscle relaxation.

3.1 Aetiology and Pathophysiology of Skeletal Muscle Cramps

While the mechanism of muscle cramps is not yet fully understood, there are some theories that try to answer that question. Currently, there are two main theories that have been proposed to explain their occurrence: the dehydration/electrolyte imbalance theory, and neuromuscular theory.^[4] Additionally, there is evidence of a genetic component in some cases, as seen in conditions such as Brody myopathy are inherited disorders impacting skeletal muscle function.

3.1.1 Dehydration/Electrolyte Imbalance Theory

The dehydration/electrolyte imbalance theory is one of the most common and long-standing theories to better understand muscle cramps.^[5] It suggests that muscle cramps during exercise, known as Exercise-Associated Muscle Cramps (EAMCs), may be related to disturbances in water and slate balance within the body.

But this theory is not conclusive as there are studies that both support and reject this theory. In one study, it was found that when athletes sweat out 20-30% of their bodily sodium ions, whether through a game, match, or training session, there is a prompt response to a severe cramp.^[1:1] Furthermore, when temperatures are increased, so does sweating, making it look like that there is a plausible relationship. A study concluded that heat cramps made up 70% of common exertional heat illness.^[6] However, this is contradicted in another study as 69% of participants still experienced EAMCs even though they were hydrated and supplemented with electrolytes.^[7] Additionally, cramps have been observed in cool environments with little or no sweat loss, indicating that factors other than sweat-induced electrolyte imbalance may be responsible for the onset of cramps.^[8] Regardless of whether or not water may help one to recover from muscle cramps, it is still required for maintaining normal physiological functions during physical activity.

While the dehydration/electrolyte imbalance theory has been a common explanation for EAMCs, it does not fully account for all instances of muscle cramps, and its limits show the need for a broader scope to understand, treat, and prevent EAMC.

3.1.2 Neuromuscular Theory

While the dehydration/electrolyte imbalance theory has been a longstanding explanation for EMACs, it is likely that there are more factors that contribute to it, which has led to the development of the neuromuscular theory. Neuromuscular theory suggests that muscle cramps are primarily caused by an imbalance in the neuromuscular control of the muscle, rather than dehydration or electrolyte imbalances. Muscle spindles are sensory receptors within the muscle that detect changes in muscle length then send excitatory signals to the spinal cord when the muscle stretches. Golgi tendon organs (GTOs) are in the musculotendinous junction, and they detect changes in muscle tension, sending inhibitory signals to the spinal cord when the muscle contracts. Normally, these signals are balanced to allow controlled muscle contraction and relaxation. But during intense exercise the muscles become fatigued, the signals that are being sent are altered. Fatigue can increase the excitatory input from the muscle spindles and decrease the inhibitory input from the GTOs, and this imbalance is what leads to a muscle cramp.^[5:1]

Like the dehydration/electrolyte imbalance theory, there are some limitations to this theory. Firstly, the theory relies on methodologies that have produced inconsistent results. For example, most GTOs afferents do not show a significant change in firing response to stretching a fatigued muscle, which challenges the idea that GTOs activity is a key factor in cramps.^[7:1] Secondly, there is no defined fatigue threshold. The theory does not say how fatigued a muscle must be for a cramp to occur. It remains uncertain whether the required level of neuromuscular fatigue is primarily peripheral (within the muscle) or central (within the central nervous system), and this threshold may vary among individuals.^[7:2] Lastly, this theory does not explain why muscle cramps occur in non-athletes. Nocturnal leg cramps (NLCs) is a condition that affects ~37% of the American population above the age of 60^[4:1], and up to 60% of adults experience NLCs.^[9] NLCs are any kind of leg cramp that occurs at night when an individual is not very active or asleep. They can wake the individual up from their sleep and make it harder for them to return to sleep.^[9:1] These night cramps can also affect one’s sleep quality and quality of life.^[4:2]

The neuromuscular theory offers a valuable perspective on the aetiology of EAMCs, but it is better to consider it within the broader context of the various factors that contribute to a muscle cramp. Further research is needed to fully understand the mechanisms behind EAMC and to develop more effective treatment and prevention strategies.

3.2.1 Pathologies Relating to Muscle Cramps

Muscle cramps can be associated with a variety of pathologies. Some of these conditions are genetic, as seen with conditions like Brody myopathy and Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps Syndrome (HANAC), which are inherited disorders affecting skeletal muscle function.

Metabolic disorders can also affect cramps. Metabolic myopathies, which affect lipid or mitochondrial metabolism, can cause muscle cramps due to disrupted energy production in muscle cells. It can cause deficiency in ATP levels, and because muscle relation is an ATP-dependent active process, actin and myosin chains do not disengage, it will cause a cramp.^[10]

Brody myopathy is a condition that affects skeletal muscle. It is a rare, autosomal, recessive, myopathy that affects about 1 in 10 million people.^[11] Affected individuals experience muscle cramping and stiffness after exercise, and the effects can worsen in cold temperatures.^[12] In some cases, exercise leads to the breakdown of muscle tissue (rhabdomyolysis), and the destruction of muscle tissue releases a protein called myoglobin, which can cause urine to turn into a red or brown colour.^[12:1] This condition is caused by mutations in the ATP2A1 gene, which encodes the SERCA1 enzyme.^[12:2] This enzyme is responsible for transporting calcium ions into the sarcoplasmic reticulum, a process crucial for muscle relaxation and mutations in the ATP2A1 gene result in a dysfunctional SERCA1 enzyme, leading to delayed muscle relaxation and cramping.^[11:1]

HANAC syndrome is inherited through an autosomal dominant pattern^[13], and is caused by mutations in the COL4A1 gene, which affect the stability of blood vessels and basement membranes throughout the body, including the kidneys, brain, muscles, and eyes.^[14] Individuals with HANAC syndrome experience muscle cramps, affecting any muscle, and like any muscle cramp, they can be spontaneous or triggered by exercise.^[14:1]

4.1 Management and Treatment Strategies

Almost every athlete has been told to do some stretching, incorporate some kind of warmup and cooldown before an exercise, or drink some water as preventative measures for cramps.^[15] However, there are very limited, and inconclusive preventative measures we can take for preventing cramps, which are just lightening our workloads like reducing training frequency and intensities^[1:2], and contrary to popular belief, there has yet to be conclusive data to show stretching can prevent muscle cramps.^[2:1] Even with treatment, there are still very limited conclusions. One of the things one could do to relieve EAMC is lengthening the affected muscle(s).^[16] There also has been some research done to prove the effectiveness of quinine derivatives, though effective, should be avoided for repetitive use due to its toxic nature.^[2:2] It has also been shown that vitamin B complex, Naftidrofuryl, and calcium channel blockers such as diltiazem may be effective in treating muscle cramps, but more investigation is needed to develop medications that are both effective and safe for the relief of muscle cramps.^[2:3]

5.1 Conclusion

Skeletal muscle cramps are involuntary, and frequently painful contractions that can significantly affect an individual’s quality of life. The understanding of muscle cramps involves a complete understanding, considering the patient’s scientific history, and muscle imbalances. The aetiology of cramps is diverse, with many physiological and pathological elements contributing to their existence. Muscle cramps may be related to a range of pathologies, along with benign leg cramps, EMACs, metabolic issues, and neurological conditions. The control and treatment of muscle cramps incorporate pharmacologic and nonpharmacologic methods. While most muscle cramps clear up on their own, they can be devastating for some people, especially athletes. It goes to show the ongoing debate surrounding the mechanisms and powerful treatments for muscle cramps, highlighting the need for similar studies in this region to enhance affected person effects and quality of life.

Bibliography

Alaia, Michael J, and Rick Wilkerson. “Muscle Cramps - OrthoInfo - AAOS,” n.d. https://orthoinfo.aaos.org/en/diseases–conditions/muscle-cramps.

Bergeron, Michael F. “Muscle Cramps During Exercise-Is It Fatigue or Electrolyte Deficit?” Current Sports Medicine Reports 7, no. Suppl. 1 (July 1, 2008): S50–55. https://doi.org/10.1249/jsr.0b013e31817f476a.

Bordoni, Bruno, Kavin Sugumar, and Matthew Varacallo. “Muscle Cramps.” StatPearls - NCBI Bookshelf, August 4, 2023. https://www.ncbi.nlm.nih.gov/books/NBK499895/.

“Brody Myopathy: MedlinePlus Genetics,” n.d. https://medlineplus.gov/genetics/condition/brody-myopathy/.

Bryn Mawr Communications. “Muscle Cramps - Practical Neurology.” Practical Neurology, n.d. https://practicalneurology.com/articles/2019-aug-july/muscle-cramps.

Chen, Zhiyong, Tiffany Migeon, Marie-Christine Verpont, Mohamad Zaidan, Yoshikazu Sado, Dontscho Kerjaschki, Pierre Ronco, and Emmanuelle Plaisier. “HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease.” Journal of the American Society of Nephrology 27, no. 4 (April 1, 2016): 1042–54. https://doi.org/10.1681/asn.2014121217.

Cooper, Earl R, Jr, Michael S Ferrara, and Steven P Broglio. “Exertional Heat Illness and Environmental Conditions During a Single Football Season in the Southeast.” J Athl Train 41, no. 3 (September 1, 2006): 332–36. http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1569552/.

Department of Health & Human Services. “Muscle Cramp.” Better Health Channel, n.d. https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/muscle-cramp.

“Hereditary Angiopathy With Nephropathy, Aneurysms, and Muscle Cramps Syndrome: MedlinePlus Genetics,” n.d. https://medlineplus.gov/genetics/condition/hereditary-angiopathy-with-nephropathy-aneurysms-and-muscle-cramps-syndrome/.

Jung, Alan P, Phillip A Bishop, Ali Al-Nawwas, and R Barry Dale. “Influence of Hydration and Electrolyte Supplementation on Incidence and Time to Onset of Exercise-Associated Muscle Cramps.” PubMed Central (PMC), June 1, 2005. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1150229/.

Katzberg, Hans D., Ahmir H. Khan, and Yuen T. So. “Assessment: Symptomatic Treatment for Muscle Cramps (an Evidence-based Review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.” Neurology 74, no. 8 (February 23, 2010): 691–96. https://doi.org/10.1212/wnl.0b013e3181d0ccca.

Maughan, Ronald J., and Susan M. Shirreffs. “Muscle Cramping During Exercise: Causes, Solutions, and Questions Remaining.” Sports Medicine 49, no. S2 (November 6, 2019): 115–24. https://doi.org/10.1007/s40279-019-01162-1.

Miller, Kevin, Marcus S. Stone, Kellie C. Huxel, and Jeffrey E. Edwards. “Exercise-Associated Muscle Cramps.” Sports Health 2, no. 4 (July 1, 2010): 279–83. https://doi.org/10.1177/1941738109357299.

Molenaar, J., Jamie I Verhoeven, Richard J. Rodenburg, Erik Jan Kamsteeg, Corrie E. Erasmus, Savine Vicart, Anthony Béhin, et al. “Clinical, Morphological and Genetic Characterization of Brody Disease: An International Study of 40 Patients.” Brain 143, no. 2 (February 1, 2020): 452–66. https://doi.org/10.1093/brain/awz410.

Physiotutors. “Muscle Cramps Explained by Science | Muscle Cramp Treatment Options,” November 19, 2021. https://www.physiotutors.com/wiki/muscle-cramps-explained/.

Professional, Cleveland Clinic Medical. “Leg Cramps.” Cleveland Clinic, n.d. https://my.clevelandclinic.org/health/diseases/14170-leg-cramps.

Schwellnus, Martin, E W Derman, and Timothy D. Noakes. “Aetiology of Skeletal Muscle ‘Cramps’ During Exercise: A Novel Hypothesis.” Journal of Sports Sciences 15, no. 3 (January 1, 1997): 277–85. https://doi.org/10.1080/026404197367281.

---

1. Michael F. Bergeron, “Muscle Cramps During Exercise-Is It Fatigue or Electrolyte Deficit?,” Current Sports Medicine Reports 7, no. Suppl. 1 (July 1, 2008): S50–55, 10.1249/jsr.0b013e31817f476a. ↩︎ ↩︎ ↩︎

2. Hans D. Katzberg, Ahmir H. Khan, and Yuen T. So, “Assessment: Symptomatic Treatment for Muscle Cramps (an Evidence-based Review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology,” Neurology 74, no. 8 (February 23, 2010): 691–96, https://doi.org/10.1212/wnl.0b013e3181d0ccca. ↩︎ ↩︎ ↩︎ ↩︎

3. Michael J Alaia and Rick Wilkerson, “Muscle Cramps - OrthoInfo - AAOS,” n.d., https://orthoinfo.aaos.org/en/diseases–conditions/muscle-cramps. ↩︎

4. Bruno Bordoni, Kavin Sugumar, and Matthew Varacallo, “Muscle Cramps,” StatPearls - NCBI Bookshelf, August 4, 2023, https://www.ncbi.nlm.nih.gov/books/NBK499895. ↩︎ ↩︎ ↩︎

5. Kevin Miller et al., “Exercise-Associated Muscle Cramps,” Sports Health 2, no. 4 (July 1, 2010): 279–83, https://doi.org/10.1177/1941738109357299. ↩︎ ↩︎

6. Earl R Cooper Jr, Michael S Ferrara, and Steven P Broglio, “Exertional Heat Illness and Environmental Conditions During a Single Football Season in the Southeast,” J Athl Train 41, no. 3 (September 1, 2006): 332–36, http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1569552/. ↩︎

7. Alan P Jung et al., “Influence of Hydration and Electrolyte Supplementation on Incidence and Time to Onset of Exercise-Associated Muscle Cramps,” PubMed Central (PMC), June 1, 2005, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1150229/. ↩︎ ↩︎ ↩︎

8. Ronald J. Maughan and Susan M. Shirreffs, “Muscle Cramping During Exercise: Causes, Solutions, and Questions Remaining,” Sports Medicine 49, no. S2 (November 6, 2019): 115–24, https://doi.org/10.1007/s40279-019-01162-1. ↩︎

9. Cleveland Clinic Medical Professional, “Leg Cramps,” Cleveland Clinic, n.d., https://my.clevelandclinic.org/health/diseases/14170-leg-cramps. ↩︎ ↩︎

10. Bryn Mawr Communications, “Muscle Cramps - Practical Neurology,” Practical Neurology, n.d., https://practicalneurology.com/articles/2019-aug-july/muscle-cramps. ↩︎

11. J. Molenaar et al., “Clinical, Morphological and Genetic Characterization of Brody Disease: An International Study of 40 Patients,” Brain 143, no. 2 (February 1, 2020): 452–66, https://doi.org/10.1093/brain/awz410. ↩︎ ↩︎

12. “Brody Myopathy: MedlinePlus Genetics,” n.d., https://medlineplus.gov/genetics/condition/brody-myopathy/. ↩︎ ↩︎ ↩︎

13. Zhiyong Chen et al., “HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease,” Journal of the American Society of Nephrology 27, no. 4 (April 1, 2016): 1042–54, https://doi.org/10.1681/asn.2014121217. ↩︎

14. “Hereditary Angiopathy With Nephropathy, Aneurysms, and Muscle Cramps Syndrome: MedlinePlus Genetics,” n.d., https://medlineplus.gov/genetics/condition/hereditary-angiopathy-with-nephropathy-aneurysms-and-muscle-cramps-syndrome/. ↩︎ ↩︎

15. Department of Health & Human Services, “Muscle Cramp,” Better Health Channel, n.d., https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/muscle-cramp. ↩︎

16. Martin Schwellnus, E W Derman, and Timothy D. Noakes, “Aetiology of Skeletal Muscle ‘Cramps’ During Exercise: A Novel Hypothesis,” Journal of Sports Sciences 15, no. 3 (January 1, 1997): 277–85, https://doi.org/10.1080/026404197367281. ↩︎