Rapamycin, mTORC1 and Exercise - Observations and Research

Almost a year ago… some material I read seemed to indicate that working out while in highest stages of rapamycin MTOR1 activation might get MTOR2 going and negatively effect the benefit of rapamycin. The idea is to get your MTOR1 clean up going with no interuption… and after half life or so… through heavy exercise starting of rebuilding with MTOR2 everything up again. Kind of see how that might be in how my veins pump and stay on.

So I only do my full gym work out on every other day. Between days I do a bit of Bench press and curls (15 minutes) . On my Rapa night - Mondays - I go to the gym after work and do my full work out… drink a glass of whole milk after to rebuild body immediately - go home grill a medium and eat with a glass of milk let it all digest a few hours (now I will add a glass of GFJ to the end of that steak meal - from what I read on GFJ). Then, at midnight - my bed time - I take my 10 mg rapa with GFJ and don’t work out at all in any manner until late Wednesday - which is later tonight. My veins turn on - pump up during the work out and will stay pumped non-stop until I do rapa again. Pic taken just now. Will add a pic tomorrow same time to demonstrate. That is what happens to me. Assume that is typical… maybe?

Hmmm… now I am a bit curious - does anybody else notice their body and circulation goes a bit dormant -hibernating when taking that blast of rapa?

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I’ve not seen anything like this in the past few years I’ve been reading, following and using rapamycin.

Some people avoid working out during the first day or two after a dose of rapamycin thinking that the rapamycin would prevent them from gaining the benefit of exercise at that point because mTORC1 is inhibited and the body needs mTORC1 activated for muscle growth and repair. But - Rapamycin is not a complete mTORC1 inhibitor by any means.

Exercise and Rapamycin use has been discussed in depth in this post:

Rapamycin and Exercise - Muscle growth inhibition

Also - it was touched upon in this discussion thread: One User Trying Very High Doses of Rapamycin

Specifically here:

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So this idea of my taking rapamycin and resting without workout activity for 2 days is in the clinical trial design of Dr. Brad Stanfield - Rapamycin Human Trial… Stop Muscle Decline in Older Adults. Link: My Rapamycin Longevity Trial Is Ready! - YouTube

His plan matches mine. Certainly these are older people doing fitness… but nothing too rigorous I would think. I do a moderate work out comprable to a fit 28 to 34 year old. My peers at the medical university gym.

So he is suggesting a trial of what I already have been doing for all most 2- years. Results in muscle maintenance and strength growth have been undeniable.

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Ah - you are right, good find!

We have his trial overview on our site here: Rapamycin Exercise Study Moves Forward: Dr. Brad Stanfield’s Study Registered in NZ

In his document he states:

Importantly when considering the combination of exercise and Sirolimus (Rapamycin), a study of sixteen healthy young males found that 16mg Sirolimus (Rapamycin) taken before resistance exercise impaired mTORC1 signalling and muscle protein synthesis after exercise [26]. This observation is important for our proposed trial design, whereby Sirolimus (Rapamycin) should be taken on a non-exercise day to maximise the time-periods where mTORC1 is switched on by exercise, and off by Sirolimus (Rapamycin).

The source he quotes is this: Activation of mTORC1 signaling and protein synthesis in human muscle following blood flow restriction exercise is inhibited by rapamycin

Its a rather extreme example in this study … the subjects were taking 16mg of rapamycin and they exercised at exactly the peak blood levels, one hour after taking the rapamycin. So - its a worst case scenario I think…

The primary purpose of this study was to determine whether mTORC1 signaling is necessary for stimulating muscle protein synthesis after BFR exercise.

We conclude that activation of mTORC1 signaling and protein synthesis in human muscle following BFR exercise is inhibited in the presence of rapamycin.

On the morning of the 1st day of the experimental trial, subjects randomly assigned to the RAP group ingested 16 mg of rapamycin 1 h prior to exercise (Fig. 1). Previously, this dosage has been validated to appear at peak concentrations in the bloodstream after 1 h and to blunt the increase in mTORC1 activation in humans in response to amino acids or high-intensity resistance exercise (8, 11) while not affecting basal muscle metabolism or basal mTORC1 signaling (7).

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DISCUSSION

The primary purpose of this study was to determine whether mTORC1 activation is necessary to increase muscle protein synthesis following acute BFR exercise. Using the mTOR inhibitor rapamycin, we show for the first time that activation of mTORC1 signaling and muscle protein synthesis following BFR exercise is impaired when rapamycin is administered to human subjects prior to exercise.

In agreement with previous studies, 16 mg of rapamycin, as used in this study, was sufficient to block the increase in the phosphorylation of mTOR and S6K1 at all time points within the RAP group. Accordingly, the concomitant increase in muscle protein synthesis following BFR exercise was also inhibited by rapamycin at all time points postexercise, indicating that the muscle protein-synthetic response is at least partially dependent on a rapamycin-sensitive pathway.

One potential limitation of administering rapamycin to human volunteers is that we are unable to provide a dosage large enough to guarantee complete inhibition of mTORC1. In fact, the rapamycin dose used in our study is much less than that commonly used in rodent experiments. Another consideration is that there are important limitations of rapamycin and its ability to completely inhibit mTORC1 signaling. A thorough treatment of this topic can be found in a recent and comprehensive review (24).

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I have blasted right through dosing with constant daily exercise. There are mTOR independent and Rapamycin independent pathways to muscle protein synthesis (several researchers in private communications). I have not seen any impact on max load, fatigue, recovery. Perhaps elite athletes might see a signal. Muscle growth is quite complicated.

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Exactly - it is complicated.

I can not even begin to compare my much smaller and reluctant workout (but I do it) to what you are doing for your kind of gains. No comparison on physical body appearence you’ve got legit muscle - I have toned - LOL. So you are defnitely in a different place. I might blast through too if I were more muscle bound. :wink:

So as promised - first image left arm after full rapa dose and rested 44 hours. Second pic arm rested but previous day work out… I will now stay veined out until my next dosing. Third pic just the other arm also now veined out. Look close and can see my poke for where I had blood drawn - had to have two sticks - how did she miss those veins (garden hoses - lol) - but she did! OUCH. I will have lab reports in a week. Thanks for the code - I had the Sirolimus test too - I want see where I am with rapa in my system at 2.5 days out. Took 10mg with GFJ on Monday night.


You need to determine what you want to be…fitness wise. Ripped and lots of muscle definition OR just fit for life. Either is OK depending on what you like. To maintain the latter is a big step down workout wise but not a great drop (or any) in “health fitness” level.

Whatever your routine the test is… test for for 3 consecutive days…4 miles in 60 minutes, 1 minute plank/rest 1 minute and repeat twice, 11 pushups (70 year old…more if younger)…look up expected grip strength and exceed high end by 10 lbs.

You can add lots of stuff to this and good to have in your workouts…most depend on your weight…but if you can do this you are “life fit”.

You can make exercise your life or part of your life.

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I commented in the earlier exercise thread that I saw a worsening of my “gas tank” on Monday evening jiu jitsu classes following my Sunday-morning rapamycin. For the last couple of months, I’ve switched from 6mg weekly to 10mg + grapefruit once every two weeks. Notably, the Monday classes following the rapamycin continue to be low-energy, while the Monday classes on non-rapa weeks are normal. This is now enough for me to be near certain that for my body and training regimen, at least, rapamycin does cause fatigue for 48 to 72 hours.

Brazilian jiu jitsu is a mix of endurance, strength and muscle endurance, with a heavy emphasis on muscle endurance. I’m currently doing 5 days of BJJ per week, but try to keep sparring sessions with partners who can push me to max HR down to 3 a week. I also do 3 days of supplemental weights (deadlifts, farmers walks, but these workouts are max 30 minutes), and 4 days of supplemental zone 2 ranging from an hour to 1.5 hours. (This requires two-a-day workouts on all days except Sunday, which is a full rest day, and one or two three-a-days for max-stimulation days.)

I’m interested in Dr. Stanfield’s trial, but that exercise routine is very relaxed. Three group fitness classes with no periodization is not going to generate many insights for athletes or anyone beyond very sedentary folks.

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Absolutely agree with this

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I concur - it doesn’t look like it would break a sweat. LOL.
I work out every other day - but it is a full hour and a half of lifting 145 to 160 pounds on 11 machines - 3 sets of 30 reps. Then 2 sets of pullups 20 each time. Then bench press 95 pounds 40 lifts and curls 20 times.Just enough to maintain what I have. I have gone up in weights about 10 pounds every 4-6 months. Pretty stable.

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Do we know why some people feel jittery and energetic after a rapamycin dose while others feel a lack of energy? My main exercise is doubles tennis, and I feel absolutely no difference between dosing and non-dosing days. Perhaps my keto diet helps me maintain the energy. I don’t think the problem is insulin resistance, since, on my dosing days, my blood glucose and exogenous insulin needs are usually lower than average.

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And some feel nothing at all. If anything, a low protein/glucose signal diet such as ketogenic should reduce mTOR, thus requiring less Rapamycin to generate inhibition.

Probably some complex genetic interaction, my complete speculation based on many studies showing large inter-person variability with dosing.

Here’s one insight, gleaned from the Glioblastoma/Rapamycin paper.

https://sci-hub.se/10.1371/journal.pmed.0050008

“Whereas this analysis highlights the importance of achieving sufficient mTOR inhibition, it fails to address the fact that adequate intratumoral rapamycin concentrations did not translate into mTOR inhibition in some patients. Such biochemical resistance could be cell-intrinsic (mutation of the drug target, expression of a drug efflux pump in tumor cells, etc.) or host-related (drug bound to serum proteins, sequestration in specific cell types or tissues, etc.)”. Remarkably, S6 phosphorylation was inhibited equally in rapamycin sensitive (patients 1 and 3) and rapamycin-resistant (patients 2 and 12) samples at 0.3 and 3.0 nM concentrations (Figure 3D), indicating that the failure to inhibit mTOR in these patients is not cell-intrinsic. Rather, the data indicate that delivery of rapamycin to tumor cells is impaired in some patients despite achieving adequate concentrations in resected brain tumor tissue. One possibility, based on the fact that rapamycin is sequestered in red blood cells [22], is that the high intratumoral concentrations of rapamycin observed in these resistant patients reflect red cell pooling in highly vascular tumors. Indeed, tumors from resistant patients showed abundant immunohistochemical staining for the vascular marker CD31 (Figure S4) but the sample size is too small to make definitive conclusions. Alternative explanations include variations in penetration of the blood–brain barrier or tumor hydrostatic pressure among patients"

Rapamycin sequestered in blood cells?

Blood Distribution in Rapamycin
https://sci-hub.se/10.1097/00007890-199311000-00029

There are also polymorphisms in mTOR genes

Meta-analysis of the association between mTORC1-related genes polymorphisms and cancer risk

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Agetron, at 7 mg once weekly I don’t notice anything as far as how I feel. I do exercises on the day of dosing the same as any other day. The only day of the week I don’t exercise is Sunday because the gym is closed. Sunday just happens to be the day after my rapamycin dose and maybe a 7 mg dose isn’t enough to create a noticeable effect for me.

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Want to clarify… although I take a gym break after rapa for about 40-44 hours… so MTOR1 restriction can clean… I don’t feel any different… no loss of energy or mood change… nothing… however, physiology of my normally pumped veins (showing high oxygenation from lungs) go shallow… until that work out… 40 hours later… then turn on full of oxygen again, and stay pumped.

Has been a pattern I noticed 6 months ago. Will expect it to happen on Tuesday morning post my rapa intake… on Monday night.

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I’m also mostly keto. I add in a bit of fruit, but it doesn’t knock me out of ketosis. And the rare times it does, I’m so fat adapted that I get back in very easily.

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Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance

“We conclude that the doses of rapamycin required to extend life do not cause overt mitochondrial dysfunction in skeletal muscle”

Just a random straggler I came across…

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