Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation.., 2021, Julian et al

Full title: Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes

Abstract

Background
Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease. ALS is determined by gene-environment interactions and improved understanding of these interactions may lead to effective personalised medicine. The role of physical exercise in the development of ALS is currently controversial.

Methods
First, we dissected the exercise-ALS relationship in a series of two-sample Mendelian randomisation (MR) experiments. Next we tested for enrichment of ALS genetic risk within exercise-associated transcriptome changes. Finally, we applied a validated physical activity questionnaire in a small cohort of genetically selected ALS patients.

Findings
We present MR evidence supporting a causal relationship between genetic liability to frequent and strenuous leisure-time exercise and ALS using a liberal instrument (multiplicative random effects IVW, p=0.01). Transcriptomic analysis revealed that genes with altered expression in response to acute exercise are enriched with known ALS risk genes (permutation test, p=0.013) including C9ORF72, and with ALS-associated rare variants of uncertain significance. Questionnaire evidence revealed that age of onset is inversely proportional to historical physical activity for C9ORF72-ALS (Cox proportional hazards model, Wald test p=0.007, likelihood ratio test p=0.01, concordance=74%) but not for non-C9ORF72-ALS. Variability in average physical activity was lower in C9ORF72-ALS compared to both non-C9ORF72-ALS (F-test, p=0.002) and neurologically normal controls (F-test, p=0.049) which is consistent with a homogeneous effect of physical activity in all C9ORF72-ALS patients.

Interpretation
Our MR approach suggests a positive causal relationship between ALS and physical exercise. Exercise is likely to cause motor neuron injury only in patients with a risk-genotype. Consistent with this we have shown that ALS risk genes are activated in response to exercise. In particular, we propose that G4C2-repeat expansion of C9ORF72 predisposes to exercise-induced ALS.

Open access, https://www.sciencedirect.com/science/article/pii/S2352396421001900

BBC News article about the study, "Motor neurone disease: Intense exercise increases risk, say scientists", https://www.bbc.co.uk/news/health-57431412

 

Yeah but since it's in the brain you can just think it away right?

 

Another example that the idea of exercise always being helpful for every illness is wrong.

 

I think this is a report of the same research on the BBC news

https://www.bbc.co.uk/news/health-57431412

Some interesting bits

more worryingly

We undergo that sort of strenuous exercise getting a drink of water. We may not have the genetics for the neurones to die but this shows that damage can be caused in the body by crossing the anaerobic threshold all the time. (My fitbit thinks I a fitter than 99% of women my age!)

 

But, but, but ... CG said that exercise makes everybody better!

Source : https://www.s4me.info/threads/paul-...les-and-other-media.15629/page-20#post-320520

 

Yes, good stuff, and for us, unsurprising. But try telling your doctors or friends or family members that exercise can and does actually hurt some people, and although they may Yes you to silence you, they don't believe it. Exercise is a Linus blanket.

It took generations to get this shit entrenched in our societal mindset, and it will take generations to properly characterize hazards and have them accepted, let alone embraced.

 

Fitbit congratulated me one day this week on my work at ‘cardio/peak’ levels
- 5 mins use of my (less than half filled) watering can on the seedlings/plants just outside the back door


PS awaiting a plumber for an outside tap for a hose

 

This is interesting. I've found that my fitbit can be an interesting objective indicator of my current physical state. A couple of times lately when I've felt unusually tired and breathless from light activity, I've looked down at my fitbit and discovered I was in the "Peak" heart rate range. Yet when I do exactly the same activity on a better day, my heart rate is hardly raised at all.

I've wondered whether this could be some way of validating what we're feeling so that we are believed...

 

Woolie, I get this too and it gives me a way of judging what my background level of ME is, if you know what I mean. I've also found that some days my heart rate is low when I would expect it to be elevated and I interpret that to mean my heart does not have the energy to beat faster so I am extra careful.

When I first got my fitbit I was amazed to discover that the times when I felt I had to lie down, now, this instant, my heart rate was higher even if it was something I usually did without a problem. That gave me the confidence to believe myself. I suppose I felt validated and had permission to believe in myself.

Years of "maybe you could just try a bit" were washed away.