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

Murph

Murph

Senior Member (Voting Rights)
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.

pubmed.ncbi.nlm.nih.gov

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 pubmed.ncbi.nlm.nih.gov
 
Murph said:
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..
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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.
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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.
 
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.
 
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.
 
rvallee said:
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.
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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.
 
poetinsf said:
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.
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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.
 
Utsikt said:
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.
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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).
 
Utsikt said:
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.
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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.
 
@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.
 
poetinsf said:
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.
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Yes it’s like the difference between cpet or bleep test too in that I’m assuming we are talking ‘leave it all on the track’ type level so you are going to the point of exhaustion and more (eg jog back recovery, sprint finishes etc)

@Yann04 s post reminded me of when the very sporty people who’d be in the hockey and netball team used to get made to do ‘at least one probably two country races’ - even though they wouldn’t have called their hockey level leisurely it didn’t mean they were trained to slog round that running course. If they’d had to do more though they’d probably have been less exhausted by the x-country as they were less wanting to be competitive at it but had a bit more practice to do the same time with less pain.

So I’m still puzzled about whether it is about the arbitrary level or eg pushing to threshold or intensity in some way.

Rather than easy training in comfort zone or a friendly match on a sunny day vs competitive level

Or leisurely is a different thing altogether. It’s a football match where people chill whilst someone gets the ball that missed and went out or a jog or hike where you chat and stop for photos

In between you’ve got what the local tennis club social tournament where you are actually playing proper matches to win or local netball clubs

And what about if you were in an informal group of mates going cycling on weekends then end up in one full of more serious people timing themselves?

Does it include golf or bowls which run for much longer per game. To be fair those are also entirely different exertions on the body if doing most of the day in bad weather of some kind vs ‘fair weather’ and take a break when you fancy etc. Or in countries where people who surf might spend the whole day out there

To be fair this is where 12hrs sounds a lot at ages where someone might work full time but otherwise through school, college, retired or part time years

It feels like there’s a middle term like people who do weights in the gym quite seriously and have a personal trainer or do tough mudder type things and the odd run at lunch time , park run etc.

Tbh 12hrs would be hard to do in running without overdoing it. Maybe the same with ‘working out’. Less so with cycling where people take eg holidays cycling through French towns or something and survive even though they do little the rest of the year? 10/12 matches would be hard to cram in and organise for most team sports , even at a tennis club and various other leisurely clubs (as most of those will be at the same time)
 
bobbler said:
So I’m still puzzled about whether it is about the arbitrary level or eg pushing to threshold or intensity in some way.
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I think they are the same thing. There is fight-or-flight factor in competition that makes you push beyond the certain level without realizing. But it still comes down to the level of intensity. If you look at the Olympic records, you'd see that the lap times come down only 5-10% when doubling the distance. That is why I say that there is an order of magnitude difference between extreme exercise of 6 hours and leisurely one of 12 hours.
 
Utsikt said:
I don’t think it was «extreme exercise of 6 hours», though. Rather, exercise of 6 hours was classified as «extreme» by the researchers.
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Huh? I thought they equated 6 hrs of extreme exercise to 12 hours of leisurely one. It doesn't make sense to say 6 hours is extreme when 12 hours is leisurely.
 
poetinsf said:
Huh? I thought they equated 6 hrs of extreme exercise to 12 hours of leisurely one. It doesn't make sense to say 6 hours is extreme when 12 hours is leisurely.
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This is how they defined the categories:
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.
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So apparently, 6 hrs pr «strenuous» = 12 hrs of «leisure-time» exercise, and both are «extreme».

I have no idea how they classified them.
 
poetinsf said:
I think they are the same thing. There is fight-or-flight factor in competition that makes you push beyond the certain level without realizing. But it still comes down to the level of intensity. If you look at the Olympic records, you'd see that the lap times come down only 5-10% when doubling the distance. That is why I say that there is an order of magnitude difference between extreme exercise of 6 hours and leisurely one of 12 hours.
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Not really

Is it a hockey player being fit but rubbishy slow st a cross country race and it straining them

Vs

Someone could be significantly faster round that course (than the hockey player is - say hundreds of metres ahead of them) but to them and their fitness for that activity feels like is actually jogging it well within their pb so not breaking a sweat


The latter would be the one you might term as leisurely but if you are measuring it by how far and times you might well get it the other way around
 
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