A Creatine-rich Diet Delays Disease in SCA3 Mice

Written by Dr. Lauren R. Moore Edited by Larissa Nitschke

Creatine, a common dietary supplement taken by athletes, delays symptoms and improves balance and strength in SCA3 mice.

Could a common nutritional supplement used by athletes to boost performance also provide benefits to ataxia patients? This was the main question addressed by a recent study of Spinocerebellar Ataxia Type 3 (SCA3), the most common dominantly-inherited ataxia in the world. The study, published in March 2018, was led by Dr. Sara Duarte-Silva at the University of Minho in Portugal. Dr. Duarte-Silva and her team investigated whether feeding SCA3 mice a diet enriched with creatine – a popular dietary supplement – improves the symptoms and brain changes that are associated with SCA3. Researchers found that a high-creatine diet delayed disease and slowed the worsening of symptoms in SCA3 mice. This study provides promising evidence that increasing or adding creatine in daily consumption may have protective benefits for SCA3 patients.

SCA3 is one of six hereditary ataxias caused by a unique type of genetic mutation known as a CAG trinucleotide repeat expansion. This occurs when a repeating sequence of three DNA nucleotides – Cytosine-Adenine-Guanine or “CAG” for short – is expanded, creating an abnormally high number of repeats. In SCA3, mutation occurs in a gene encoding the protein ATXN3 and produces an abnormally long “sticky” region in the disease protein. This sticky region, called a polyglutamine expansion, impairs ATXN3’s normal functions and causes it to build up in brain cells as toxic protein clumps. As a result, the brain’s ability to make and store energy is often impaired in SCA3 patients (a deficit that is also seen in many other brain disorders). Thus, drugs or compounds that improve overall energy production and use in brain cells could be beneficial in SCA3 and other ataxias.

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One such compound that may increase energy efficiency – particularly in the brain and muscles – is creatine. Creatine is made naturally by the body, but can also be consumed through foods like red meats and seafood. In addition, creatine is a common ingredient in many commercially-available dietary supplements that claim to improve athletic performance by boosting energy and building muscle. Creatine has recently been shown to have some benefits in mouse models of other brain diseases with similarities to SCA3. However, whether creatine could benefit SCA3 patients hadn’t been investigated prior to this study.

To assess whether increased creatine consumption could be helpful for SCA3, researchers performed a study using a mouse model of SCA3. The brains of these mice produce the mutant protein that causes SCA3, which causes them to show many of the same symptoms that occur in actual ataxia patients: muscle weakening, poor balance, and tremors start to appear around “early adulthood” in the life of a mouse. SCA3 mice were given either normal food or food supplemented with an additional 2% creatine starting at 5 weeks of age and continuing up to 34 weeks. Throughout the trial, mice were put through a series of obstacle course-like motor tests to determine whether the creatine-enriched food had a positive impact on their ataxia-related symptoms.

Researchers observed overall improvements in muscle strength, balance, and coordination at the end of trial, pointing to potential benefits for both the brain and muscles of SCA3 mice. By measuring the force that mice could grip a wire every two weeks, researchers found that SCA3 mice receiving a high-creatine diet were stronger compared to SCA3 mice receiving a normal diet. Additionally, the creatine diet delayed the appearance of muscle weakness in SCA3 mice. With a normal diet, weakness onset occurred in SCA3 mice at 12 weeks; however, with a high-creatine diet, weakness onset occurred at 20 weeks. In terms of a mouse’s lifespan, this eight-week delay is quite considerable. The creatine-enriched diet also led to some improvements in two balance beam-based physical tests and greatly increased SCA3 mice’s swimming speed, a measurement of both strength and coordination. By the end of the trial, creatine-treated SCA3 mice were swimming just as quickly as non-SCA3 mice.

Next, investigators assessed whether the symptomatic benefits of creatine coincided with improvements in brain regions that are known to be affected in SCA3 (many of which are involved in fine movement control and balance). As expected, SCA3 mice that received normal food showed a decreased number of Purkinje cells, a type of neuron in the cerebellum that is critically important for balance. Creatine-treated SCA3 mice, on the other hand, did not experience this Purkinje cell loss – in fact, by the end of the trial, the number of Purkinje cells in creatine-treated SCA3 mice was indistinguishable from the number of Purkinje cells in non-SCA3 mice. Thus, creatine successfully prevented any observable cell death. The creatine-enriched food also prevented signs of damaging inflammation that occur the brains of both SCA3 patients and SCA3 mice. In addition, there appeared to be reduced amounts of the mutant disease protein in the brains of creatine-treated SCA3 mice, which could point to improvements in the brain’s ability to prevent build-up of toxic proteins over time.

Importantly, creatine was found to be safe and well-tolerated by all mice in this study. Over-the-counter creatine as an oral supplement is also considered generally safe in humans with few potential side effects. However, some evidence suggests creatine may contribute to kidney damage, and therefore people with kidney disorders should speak with their physician before taking creatine.

Overall, mice receiving the creatine-supplemented food showed a later onset of disease symptoms and a slower worsening of symptoms over time without any negative side effects detected. The findings of this study are similar to promising results from another trial that assessed a high-creatine diet in a mouse model of Huntington’s disease, a disorder that shares many symptoms and genetic features with SCA3. Both of these studies used a creatine dose that is approximately equal to three grams per day for humans, which is well below the daily amount typically used by athletes for sports and training purposes. Importantly, improvements in motor performance and strength following creatine treatment in models of two different brain diseases support that creatine may generally promote brain and muscle health, and thus may be beneficial for other ataxias, as well.

At this time, no clinical trials have been performed to assess whether creatine has beneficial effects in SCA3 patients, so it is unclear whether the improvements observed in this mouse study would translate to humans. In addition to answering the most basic question – would creatine supplements benefit SCA3 patients – human clinical trials are needed to answer other critical questions. For instance: when should patients begin taking creatine? Or, what’s the correct daily dose of creatine for SCA3 patients? Before creatine could become an approved and neurologist-recommended medication for SCA3 patients, all of these would need to be addressed.

Several human clinical trials assessing creatine have been performed for other brain disorders, including Parkinson’s disease, ALS, and Huntington’s disease. So far, results have been somewhat conflicting. In one clinical trial, creatine supplements appeared to reduce the loss of brain cells in Huntington’s patients, but did not lead to any considerable improvements in motor or cognitive symptoms. Thus, creatine likely had some, albeit modest, benefits for these patients. On the other hand, in several large clinical trials, creatine supplements led to no measurable improvements in patients with Parkinson’s disease or ALS. Regardless, the safety profile of creatine and growing experimental evidence supporting its potential benefits point to the need for future studies of creatine-based therapies for SCA3.

Key Terms

Creatine: An amino acid (the molecular building blocks of proteins). Creatine is produced naturally by the body’s kidneys, pancreas, and liver, though it is also found in red meat and seafood. In humans, creatine is most abundant in the muscles and the brain, where it is stored and subsequently broken down for energy. As a dietary supplement, creatine supplements are typically marketed as a way to improve athletic performance by boosting energy and helping build muscle mass (though clear evidence supporting these health benefits is limited).

Purkinje cells: A type of brain cell located in the cerebellum that plays important roles in regulating and coordinating movement. Dysfunction or loss of Purkinje cells is a common cause of motor symptoms in many different types of ataxia.

Conflict of Interest Statement

The author and editor declare no conflict of interest. Dr. Patrícia Maciel, who completed the work described in this article, is a contributor to SCAsource. Dr. Maciel did not have any contribution to the writing or editing of the article.

Citation of Article Reviewed

Duarte-Silva, S., et al., Neuroprotective Effects of Creatine in the CMVMJD135 Mouse Model of Spinocerebellar Ataxia Type 3. Mov Disord., 2018. 33(5): p. 815-826. (https://www.ncbi.nlm.nih.gov/pubmed/29570846)