Paradigm shift now considers exercise a potent therapy for multiple sclerosis
This web page was produced as an assignment for an undergraduate course at Davidson College.
Until recently, the prior consensus was that exercise for multiple sclerosis patients was detrimental due to the heat sensitivity and potential aggravation of symptoms; however, exercise in acute amounts, is now recommended because it has proven to improve outcomes of both physical fitness such as fatigue and in central nervous system related outcomes such as cognition.
Multiple sclerosis is an inflammatory neurodegenerative disorder in which immune cells enter the central nervous system and destroy myelin, neurons, and axons.^1 Myelin is simply an insulating layer that surrounds nerves and allows electrical signals to transmit efficiently and quickly along the axon.^2 Such destruction can result in significant mental and physical symptoms, especially muscle weakness, abnormal walking mechanics, balance problems, spasticity, fatigue, cognitive impairment and depression. It is estimated that 1 million adults in the United States are diagnosed with this disease and that it inflicts more than 2.3 million people worldwide.^3 Given the high likelihood for disability and decreased neurological function, there have been concerns about patients exercising. However, recent studies are concluding that exercise improves cognition, fatigue, depression and mood in multiple sclerosis patients.
The goal of this research team was to increase and expand their understanding of the mechanisms of multiple sclerosis and the role exercise could play in therapy, in order to motivate multiple sclerosis patients to embrace exercise, a current barrier. Therefore, their research question was can short bouts of exercise influence the peripheral blood and central nervous system of mice with induced spinal cord demyelination?
In order to study this, they first subjected mice to acute amounts of exercise and compared them to a sedentary control who were placed in an environment with a locked wheel. Mice in the experimental group would run during their night cycle over the four day period. They discovered 115 upregulated proteins in the non lesioned naive running michelin protein involved with membrane trafficking, extracellular matrix, metabolism and myelination and 67 significantly downregulated. Therefore; these findings suggest that acute exercise in naive mice can alter both the central nervous system and serum proteomes. Similarly, they then determined whether the demyelinated experimental mice had altered proteomes in response to exercise. To model the environment of such a demyelinated multiple sclerosis lesion, mice were injected with lysolecithin, a compound that reduces the ability of fatty acids to bind.^4 After confirmed demyelination, spinal cords and serum were subjected to tandem mass tag labeling shotgun proteomics to identify altered protein levels. 86 proteins were significantly upregulated and 85 were highly down regulated in the spinal cord. In serum, 16 were upregulated and 11 were down regulated. The key altered pathways in these findings were contained within the oxidative stress response, metabolism and transmission across chemical synapses. All in all, providing evidence that acute amounts of exercise are sufficient to profoundly alter the proteome of the spinal cord and serum in both wildtype and demyelinated model mice.
This demonstrates that access to voluntary running wheel activity over four days is sufficient to induce significant protein level changes within the lesioned spinal cords associated with oxidative stress, metabolism, neurotransmission and proteolytic remodeling of the extracellular matrix. Such a result brings about many benefits of exercise some of which include: release of anti inflammatory myokines, activity of anti inflammatory microglia, neurogenesis and gliogenesis, remyelination, increase of blood levels of myeloperoxidase (recruiting macrophages to damaged sites,) and increase of neuroactive metabolites such as acetylcholine. The latter of which positively linked exercise to mental health and antidepressant activity. These benefits are of serious signficance in the everyday lives of patients inflicted with such a debiliatating disorder.
Despite these exciting findings, several key limitations need to be discussed First of all, the sample sizes of both groups were small. The first study was just 8 female mice. With that, the sex of the mouse also may confound the results; hence, I would want to repeat this study in male rodents. I would also be interested to use a different technology to assess the proteins present because mass spectrometry is not always solely reliable This could be coupled with this research to make the findings more valid and widespread. Another major source of limitation is in the inability of our demyelination model to completely replicate every facet of the disease. In reality, it is just a toxin induced injury that lacks all the other aspects of the disorder and this results in the death of the adaptive immune response, which is a serious shortcoming. Although lymphocytes have been shown to be present early in lesion formation, the short lifespan and focal nature of the lesion restricts the immune response to an innate one.
Because of these limitations, I reveal a couple of areas of future research. First, despite the increased knowledge of the mechanisms of exercise, it is not known how quickly they are affected; therefore, I would like to investigate the speed at which these benefits are observed and then also how long they last after the exercise protocol. Would these proteomic changes appear after just a single running episode and would they last well beyond the termination of exercise? And finally, I would like to further explore this concept of MedXercise that combines multiple treatments and assess its efficacy. In summary, this research provides a protein level landscape of how exercise alters the central nervous system in a naive or wildtype mouse and also in a multiple sclerosis model. The rapid elevation of the numerous proteins involved in several pathways is extremely significant and provides an exciting grounds to pursue new questions and potential treatments.
References.
Halabchi F, Alizadeh Z, Sahraian MA, Abolhasani M. Exercise prescription for patients with multiple sclerosis; potential benefits and practical recommendations. BMC Neurol. 2017 Sep 16;17(1):185. doi: 10.1186/s12883-017-0960-9.
Motl RW. Exercise and Multiple Sclerosis. Adv Exp Med Biol. 2020;1228:333-343. doi: 10.1007/978-981-15-1792-1_22.
Reynolds ER, Ashbaugh AD, Hockenberry BJ, McGrew CA. Multiple Sclerosis and Exercise: A Literature Review. Curr Sports Med Rep. 2018 Jan;17(1):31-35. doi: 10.1249/JSR.0000000000000446.
Waxman SG. Demyelination in spinal cord injury. J Neurol Sci. 1989 Jun;91(1-2):1-14. doi: 10.1016/0022-510x(89)90072-5.
Taylor Mingle is a senior at Davidson College expected to graduate with a Bachelor’s degree in Biology in May 2021. Contact her at tamingle@davidson.edu
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