Frequent, Intense Exercise May Promote ALS in Those With Risk Genes
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Strenuous, intense exercise done frequently is an environmental risk factor for amyotrophic lateral sclerosis in people with ALS risk genes, particularly those who carry a faulty C9ORF72 gene, a study concluded.
Future research is needed to better understand and identify people at disease risk due to such exercise, 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 markedly outweigh the risks,” they wrote. But in this study of ALS patients with and without genetic vulnerability, “we discovered that ALS risk genes are differentially expressed [their activity is more or less] following exercise” done intensely and repeatedly.
The study, “Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, 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 they 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 younger age than the general public, suggesting exercise as an ALS environmental risk factor.
Studies examining exercise history in ALS patients, however, show conflicting results, mainly due to data drawn from questionnaires of various types of exercise across general patient groups, the study noted. Inaccurate recall of past exercise and the lack of a controlled selection of study patients, with their different disease characteristics, introduced bias into these investigations that affected their results.
Still, an association between ALS risk 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 with the University of Sheffield in the U.K., 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 single genetic changes — small nucleotide polymorphisms (SNPs) — that correlated with disease. SNPs that associated with various forms of exercise were also identified, allowing a relationship between exercise and ALS to be assessed.
Frequent and strenuous physical activity was the study’s focus, as the motor neurons most vulnerable in ALS engage muscle fibers responsible for short bursts of activity under anaerobic (non-oxygen) conditions.
Questionnaires completed by U.K. Biobank (UKB) participants identified those who engaged in strenuous exercise, and those SNPs associated with regular “strenuous sport or other exercise” (SSOE) — defined as two to three days per week or more in exercise, for at least 15 to 30 minutes. People less physically active — or largely inactive — served as controls. In total, 124,842 active people and 225,650 controls made up this study phase.
Using Mendelian randomization to eliminate most of the biases found in previous studies, the team discovered a genetic liability to SSOE that was positively associated with ALS.
“This result is consistent with a causative relationship between frequent and strenuous exercise, and ALS which is not confounded by selection or recall bias,” the team wrote. “The association is driven primarily by a deleterious effect of exercise on motor neuron health.”
Movement independent of exercise was also measured, via an accelerometer worn for one week by some UKB participants. Movement on its own, including an occasional “strenuous sport,” did not associate with ALS. This was “consistent with the hypothesis that risk of ALS is linked to frequent and intense leisure-time physical activity,” the researchers wrote.
Sedentary behavior was also not show to significantly protect against ALS, and the link between physical exercise and ALS was not affected by a person’s percentage of body fat — body mass index — or education level.
Researchers next investigated how exercise affected the activity (expression) of ALS risk genes. By measuring changes in gene activity in blood immune cells 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 ALS-associated variants, including the “ALS signaling pathway.” (A signaling pathway refers to a series of reactions carried out by certain molecules in a cell to control cellular functions, like division or intentional cell death.)
Consistently, 52% of genes with a validated connection to ALS, including C9ORF72, were differentially expressed following exercise, and this enrichment was statistically significant.
The study’s third part used a questionnaire to examine historical physical activity in 17 adult ALS patients with disease-related C9ORF72 alterations, compared with an age- and sex-matched control group of 34 patients without these C9ORF72 variants, and a control group of 34 neurologically healthy people.
Results showed disease onset at younger ages in ALS patients with C9ORF72 variants and a history of greater physical activity. No such association was observed in those without C9ORF72 alterations.
“In our model, an individual carrying a C9ORF72 expansion is likely to develop ALS when they receive a certain ‘dose’ of exercise,” the researchers wrote.
Lesser variability in average physical activity was also seen in ALS patients with that common genetic risk factor than in those without it or in healthy controls, supporting strenuous and frequent physical activity as an environmental risk, especially for C9ORF72 variant patients.
“In conclusion, the current evidence supports a complex causal relationship between physical exercise and ALS,” the investigators wrote.
“We have used two-sample MR [Mendelian randomization] to establish the basis for frequent and strenuous leisure-time exercise as a risk factor for ALS and we have also developed understanding of the specific genetic subtypes of ALS which may be responsible for this interaction,” they added.
But exercise is not “one homogeneous exposure; in reality different types of exercise can impact different biological pathways and even different subtypes of motor neurons,” they continued. “Consistent with this, our MR study does not support a causal role for low-intensity, infrequent exercise, but does support toxicity resulting from high-intensity, frequent, leisure-time exercise.”
Future research, the study concluded, needs “to understand which individuals are at risk of developing ALS if they exercise excessively and provide appropriate lifestyle counselling. Our work goes some way towards developing this aim and in particular, we propose that C9ORF72 penetrance [the likelihood it will cause disease] may be influenced by high levels of physical activity.”
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