Extreme exercise in males is linked to mTOR signalling and onset of amyotrophic lateral sclerosis (O'Brien et al 2025)

[Murph]

Brain

2025 Jun 18:
doi: 10.1093/brain/awaf235. Online ahead of print.

Extreme exercise in males is linked to mTOR signalling and onset of amyotrophic lateral sclerosis​

David O'Brien et al, University of Sheffield

Amyotrophic lateral sclerosis (ALS) is thought to be caused by interaction between genetic and environmental factors leading to motor neuron (MN) degeneration. Physical exercise has been linked to ALS but controversy remains. A key question is to determine which individuals might be at risk of exercise-associated ALS, because unnecessary avoidance of exercise could be harmful.

We implemented complementary strategies including Mendelian randomization and multiple questionnaire-based measures of physical exercise in different cohorts. We include a prospective study in UK Biobank participants where we could test for a relationship between exercise and the timing of future ALS symptom onset. To interrogate the molecular basis of our observations we performed a genetic association study of 'extreme' exercise, equivalent to >6 hours of strenuous exercise or >12 hours of any leisure-time exercise per week.

Our data suggest that the link between increased physical exercise and ALS is particularly important for males who perform the most activity; with no evidence of a link in females. We determined that extreme exercise in males is associated with loss-of-function genetic variants within a number of mammalian target of rapamycin (mTOR) signalling genes that are also differentially expressed in ALS spinal cord.

Activity-induced mTOR signalling has been shown to selectively benefit MN. Therefore, our findings could imply that moderate exercise is neuroprotective via enhanced mTOR signalling, but extreme exercise in men is associated with neurotoxicity and ALS via a failure of this mechanism. There was no significant overlap between genes associated with extreme exercise and those associated with ALS risk, consistent with a true gene-environment interaction rather than a shared genetic basis. We are not yet able to make individual-level recommendations regarding exercise and risk of ALS, but our conclusions should focus future investigation.

Extreme exercise in males is linked to mTOR signalling and onset of amyotrophic lateral sclerosis - PubMed

Amyotrophic lateral sclerosis (ALS) is thought to be caused by interaction between genetic and environmental factors leading to motor neuron (MN) degeneration. Physical exercise has been linked to ALS but controversy remains. A key question is to determine which individuals might be at risk of...

pubmed.ncbi.nlm.nih.gov

 

[Murph]

Just thought this was an interesting one, you never see the medical establishment publish anything against exercise, but this study looks quite well-powered to draw the (limited) conclusions it draws..

 

[rvallee]

Just thought this was an interesting one, you never see the medical establishment publish anything against exercise, but this study looks quite well-powered to draw the (limited) conclusions it draws..

They have gotten around it by labeling exercise frequency at or below typical recommendations as extreme:

To interrogate the molecular basis of our observations we performed a genetic association study of 'extreme' exercise, equivalent to >6 hours of strenuous exercise or >12 hours of any leisure-time exercise per week.

There are many guidelines that recommend more than this as a baseline. Without any basis, of course, but here they work around the problem of finding their panacea not being universally wonderful by misrepresenting it.

How does someone think that 6 hour of strenuous exercise is equivalent to 12 hour of leisurely pace? No idea, but I'm sure it makes sense if you don't think about it.

 

[Kitty]

Interesting, I've long wondered about this.

It could be a statistical mirage, but the number of sportsmen diagnosed in their 40s with motor neurone disease really sticks out. They're not all famous or even professional, you sometimes see reports popping up in local news.

 

[Yann04]

I’d be interested in seeing if there is any correlation and what its characteristics may be between ME and ALS.

But I suspect we wont get any useful data on that until ME is defined as a mechanism and not a syndrome, because people woth ALS/MND feeling ill will just be attributed to the ALS.

 

[poetinsf]

How does someone think that 6 hour of strenuous exercise is equivalent to 12 hour of leisurely pace? No idea, but I'm sure it makes sense if you don't think about it.

This was my first thought. The difference between the two is an order of magnitude. People who can hike for 12 hours a day won't be able to run for 30 min unless he trained for it. A super-fit newbie won't last 30 sec when wresting either.

 

[Utsikt]

difference between the two is an order of magnitude. People who can hike for 12 hours a day won't be able to run for 30 min unless he trained for it.

I think that’s a bit or an exaggeration. Hiking 12 hrs/day will be beneficial for your cardio. You’d probably not do very well in a sprint, but I suspect they’d do just fine in a marathon or half.

What I don’t understand is how 6 hrs of exercise a week is considered «extreme». I did more in grade school just through organised sports.

 

[Yann04]

I think that’s a bit or an exaggeration. Hiking 12 hrs/day will be beneficial for your cardio. You’d probably not do very well in a sprint, but I suspect they’d do just fine in a marathon or half.

What I don’t understand is how 6 hrs of exercise a week is considered «extreme». I did more in grade school just through organised sports.

I think it depends.

I’ve had levels of fitness where I could hike all day and climb 1500+ meters in altitude but I couldn’t run past 5-7k. In fact it gave me almost pem like symptoms (that were short lasting) when I tried running. (This was pre-ME/CFS but maybe a “premorbid stage” so hard to know if my anecdote would apply to healtrhy people).

 

[poetinsf]

What I don’t understand is how 6 hrs of exercise a week is considered «extreme». I did more in grade school just through organised sports.

That's how I ended up with ME/CFS, by wrestling 4 days a week for 90 minutes each in ripe middle age. That was when I was able to hike 12 hours a day for days on end. The toll judo took on me was on entirely different level. I'm experiencing the similar now in the recovery stage of ME/CFS. Just taking a few more steps per min makes me keel over when I'm under the weather. Distance doesn't.

 

[jaded]

@poetinsf - Interesting you did Judo as it’s a very physically demanding sport at any age that I’m not sure many people quite appreciate due to all muscle groups used and the stamina required.

I used to train 2-3 times a week after school and competitions all over the country at weekends from ages 4-12 when I finally became a national judo champion in the U.K after being at the top of my game for years. I had to pull out despite being on track for the Youth Olympics as a non-specific virus triggered ME. I was never the same again endurance wise but could eventually handle a lower impact “sport” like ballet.

But I’ve continued to decline with each viral/immune trigger and can barely walk 50 metres now, 2 years ago I couldn’t even sit up in bed and was spoon fed. I’ll never know if the intensive exercise pre-disposed me to it at the time but there seems to be a lot of coincidences occurring like this.