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Frequent, intense exercise may promote ALS in people with genes at risk

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Frequent strenuous and strenuous exercise is an environmental risk factor for amyotrophic lateral sclerosis in people with risk genes for ALS, especially those who carry an C9ORF72 gene, a study concluded.

Future research is needed to better understand and identify those at risk for disease from such exercises, and to develop appropriate lifestyle advice for them and their families, its researchers said.

“It is clear that, for the majority of individuals, the health benefits of a physically active lifestyle clearly outweigh the risks,” they wrote. But in this study of patients with ALS with and without genetic vulnerability, “we found that ALS risk genes are differentially expressed. [their activity is more or less] after exercise ‘done intensely and repeatedly.

The study, “Exercise is a risk factor for amyotrophic lateral sclerosis: converging evidence from Mendelian randomization, transcriptomics and risk genotypes, ”Was published in the journal EBioMedicine.

A progressive disease, ALS is characterized by the death of motor neurons that control voluntary muscles. Mutations in several genes are associated with familial ALS and are known to contribute, along with environmental risk factors, to sporadic ALS.

Professional athletes are also known to develop ALS at a higher rate and at a younger age than the general public, suggesting that exercise is an environmental risk factor for ALS.

Studies examining the history of exercise in patients with ALS, however, show conflicting results, mainly due to data from questionnaires on various types of exercise in general patient groups, the study noted. The inaccurate recall of past exercise and the absence of a controlled selection of patients in the study, with their different disease characteristics, introduced bias into these investigations which affected their results.

However, an association between the risk of ALS and exercise has often been reported in people with a high incidence of alterations in the C9ORF72 gene, the most common genetic risk factor for ALS.

Researchers at the University of Sheffield in the UK, in a three-part study, assessed exercise as an environmental risk factor for ALS.

First, they used publicly available genome-wide association study (GWAS) data to look for unique genetic changes – small nucleotide polymorphisms (SNPs) – that correlated with the disease. SNPs associated with various forms of exercise have also been identified, making it possible to assess a relationship between exercise and ALS.

The study focused on frequent and intense physical activity, as the motor neurons most vulnerable in ALS engage muscle fibers responsible for short periods of activity under anaerobic (oxygen-free) conditions.

Questionnaires completed by UK Biobank (UKB) participants identified those who engaged in strenuous exercise and SNPs associated with regular ‘sport or other strenuous exercise’ (SSOE) – defined as two to three days per week or more exercise, for at least 15 to 30 min. People who were less physically active – or largely inactive – served as witnesses. In total, 124,842 active people and 225,650 witnesses made up this study phase.

Using Mendelian randomization to eliminate most of the biases found in previous studies, the team found a genetic liability to SSOE that was positively associated with ALS.

“This result is consistent with a causal relationship between frequent and intense exercise, and ALS that is not confused by selection or recall bias,” the team wrote. “The association is primarily due to a deleterious effect of exercise on motor neuron health.”

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Independent exercise movement was also measured, via an accelerometer worn for a week by some UKB participants. Movement alone, including occasional “strenuous sport”, was not associated with ALS. This was “consistent with the hypothesis that the risk of ALS is linked to frequent and intense physical activity during leisure time,” the researchers wrote.

Sedentary behavior was also shown to not significantly protect against ALS, and the link between exercise and ALS was not affected by body fat percentage – body mass index – or level of exercise. education of a person.

The researchers then studied how exercise affected the activity (expression) of ALS risk genes. By measuring changes in gene activity in immune cells in the blood after exercise, they identified 323 biological pathways that are expressed differently in response to intense exercise.

Notably, 72 pathways (22%) were significantly enriched with rare variants associated with ALS, including the “ALS signaling pathway”. (A signaling lane refers to a series of reactions performed by certain molecules in a cell to control cell functions, such as intentional cell division or death.)

Consistently, 52% of genes with a validated connection to ALS, including C9ORF72, were expressed differently after exercise, and this enrichment was statistically significant.

The third part of the study used a questionnaire to examine the historical physical activity of 17 adult patients with ALS with the disease C9ORF72 alterations, compared to a control group matched by age and sex of 34 patients without these alterations C9ORF72 variants, and a control group of 34 neurologically healthy people.

The results showed the onset of the disease at younger ages in ALS patients with C9ORF72 variants and a history of greater physical activity. No such association was seen in people without C9ORF72 modifications.

“In our model, an individual with a C9ORF72 expansion is likely to develop ALS when given a certain ‘dose’ of exercise,” the researchers wrote.

Less variability in mean physical activity was also seen in patients with ALS with this common genetic risk factor than in those without or without it. healthy controls, supporting intense and frequent physical activity as an environment risk, especially for C9ORF72 variant patients.

“In conclusion, the current evidence supports a complex causal relationship between exercise and ALS,” the investigators wrote.

“We used two-sample MRI [Mendelian randomization] to establish the basis for frequent and intense recreational exercise as a risk factor for ALS and we have also developed an understanding of the specific genetic subtypes of ALS that may be responsible for this interaction, ”they added.

But exercise is not “a homogeneous exposure; in fact, different types of exercise can impact different biological pathways and even different subtypes of motor neurons, ”they continued. “In accordance with this, our MR The study does not support a causal role for low-intensity, infrequent exercise, but does support toxicity resulting from frequent, high-intensity recreational exercise.

Future research, the study concluded, must “understand who people are at risk for developing ALS if they exercise excessively and provide appropriate lifestyle advice.” Our work goes to some extent towards the development of this objective and, in particular, we propose that C9ORF72 penetrance [the likelihood it will cause disease] can be influenced by high levels of physical activity.


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