I have wondered about rapamycin, mTOR inhibition, protein consumption, and weight lifting. I am on a high protein diet, and I lift heavy – with my first session of the week often coinciding with the likely peak of my weekly dose of rapamycin. I always wondered if it was nonsense to lift weights and eat big protein meals while taking rapamycin. So I was very intrigued by Stuart Phillips’s comments in this interview with Rhonda Patrick. It seems like he is saying that there are two channels for muscle growth, with one mediated by mTORC1 and the other by mTORC2. I thought there would be some interest on this forum.
leucine → mTORC1 up → muscle protein synthesis → small impact on muscle growth
resistance training → mTORC2 up → big impact on muscle growth
Maybe I am hearing what I want to in this, but it sounds like combining rapamycin, protein, and lifting might not be crazy. My guess is that the rapa impact on mTORC1 dominates the leucine impact on mTORC1 without losing much effect along the way.
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Here is a useful paper
“ West et al. demonstrated that mTOR inhibition through rapamycin inhibited 6 h postexercise muscle protein synthesis after sciatic stimulation of the hindlimb muscles in rats. However, rapamycin only partially inhibited protein synthesis 18 h after exercise,…”
https://journals.physiology.org/doi/full/10.1152/physrev.00039.2022
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mccoy
#3
I too have been often wondering about the role of mTOR in muscle hypertrophy and metabolism in general. As a general rules and as well known by those who have lifted weights, mTOR in skeletal muscles is maximally activated by maximizing the nutrient signal (energy, glucose→insulin→GF-1, Leu+other EAAs) AND the mechanic signal (loading). In this discussion supraphysiological androgen concentrations are excluded.
Maximum activation however entails maximum phosphorylation of all the downstream proteins : those that rule MPS and those that rule adipocytes growth.
The result is muscle hypertrophy plus growth in fat tissue. It is inevitable, as far as I know.
Conversely, when we want to loose adiposity, we must dim the mTOR pathway, by providing less energy, less nutrients signal. This almost inevitably brings about a breakdown in adiposity but also in muscle protein. All we can do is, sadly, to adjust the ratio of lean to fat mass by providing more mechanic signaling and protein signaling and less energy. Nevertheless, we are going to lose some muscle mass. In all my life, I’ve never been able to lose adiposity and save muscle mass. Never.
Apparently, mTOR is like a cat, if we pull its tail, we pull the whole cat, the muscle, the fat, the organs, the skeleton.
All the above to try and provide actionable suggestions to how to minimize muscle loss while fasting, while in a CR period, while on Rapamycin.
I have yet to watch the video and to read the article posted, I’m going to do it soon.
In the following figure from the above article, it is illustrated how mechanotransduction activates mTOR by the upstream signals: Phospholipase D (PLD), phosphatidic acid ¶. The figure also illustrates the differences between resistance and endurance exercise.
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mccoy
#4
The following is a brief explanation of one mechanotransduction model, as per a simple AI research. It would turn out that the mechanical signal at least in part acts on the PI3K-Akt pathway, in a manner similar to the insulin/IGF-1 signal
It is not clear if this mechanism is relevant to the cardiac muscle or to skeletal muscle as well
Stretch-Activated Channels and mTOR in Muscle Cells
Stretch-activated channels (SACs) are a family of ion channels that open in response to mechanical deformation of the cell membrane. These channels play a critical role in sensing and responding to mechanical stimuli, such as muscle contraction and stretching.
How SACs activate mTOR in muscle cells:
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Mechanical Stimulation: When muscle cells are stretched or contracted, the cell membrane is deformed, leading to the opening of SACs.
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Ion Influx: The opening of SACs allows the influx of ions, such as calcium and sodium, into the cell.
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Intracellular Signaling: These ions can activate various intracellular signaling pathways, including the PI3K-Akt pathway.
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Ray1
#5
I think Rapamycin will be recognized as a performance enhancing drug in older athletes. Within a few years all of the top competitors at the Senior Games will be taking Rapamycin if it is not banned.
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Agetron
#6
Yes, because you can actually measure for rapamycin (Labcorp)in the blood, it will be hard to hide the fact of those that are dosing.
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mccoy
#7
This is the article outlined by Rhonda Patrick when Phillips is talking about exercise activating mTOR2 more than mTOR1 (a fact that I never heard about before and to be searched for more evidence).
Also, I’m just browsing the article posted by Joseph Lavelle and it seems to go pretty down into the detail of mechanical signaling, I’m going to dissect it later
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Ah, but they would only need to stop dosing a few weeks prior to a competition for it to be down to undetectable levels… so even if they check, they won’t find anything…
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Agetron
#9
True, true, so my four years of dosing would be negligible after a couple weeks of being off. And that’s the benefit of using a natural microbe molecule that goes to all thirty eight trillion cells does its job and vanishes much like food.
Only my regenerated and stronger physiology would be present as evidence… good genetics. Hahaha.
mccoy
#10
The 1st figure of the article coauthored by Phillips, 2022, illustrates , according to the authors, the different contributions to hypertrophy of the external variables:
Internal factors triggered by external variables= max contribution
Resistance exercise= max external contribution
Diet (probably isocaloric and similar protein content) =2nd external contribution, much less than RE
Sleep= 3rd external contribution, a little less than diet
Supplements= 4th and last external contribution, the smallest one.
It is evident the overwhelming contribution to hypertrophy of internal variables, depending (likely) on individual variability and genetic setup. It is well known that there are good responders and bad ones to RE.
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mccoy
#11
I’ve searched the article and there are 5 references to mTORC2, but there is no reference to the putative distinct pathway where mTORC2 would respond to RE, as told by Phillips in the podcast. Maybe he was just speculating, or talking about some work in progress.
In the following figure, the same article, the upstream signals, including mechanic stress, are outlined. It is interesting to notice that two different paths downstream of the mechanical signal (the costamere-propagated cgamma1-FAK and the Ras–MEK–ERK 1/2 signaling) converge toward the same two translational initiation factors, rpS6 and elf4B).
The above, if I’m not wrong, means that, since the Ras–MEK–ERK 1/2 cascade is independent of mTOR, even in the presence of the FKBP12 -rapamycin complex, the mechanical signal can trigger some translational processes.
This would explain at least in part the possibility of MPS even after the administration of Rapamycin, although in a less potent way.
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mccoy
#12
In the Roberts et al., 2023 (coauthored by Philips) article, the authors go into the minutiae of mechanical signaling. In figure 5, it’s interesting that 3 different mechanotransduction candidates are proposed
edit:
Based on the above able, we would be able to choose and prioritize the interventions favourable to muscle hypertrophy.
1-Resistance exercise is king. We should give utmost importance to develop an individualized training strategy to optimize it. I can think of no better material than Brad Schoenfeld’s book “Science and Development of muscle hypertrophy”. The gist of it is that, from a few reps to about 30 reps, whatever loadings, providing we go to failure and adopt enough volume, will contribute to hypertrophy.
2-Supplements appear to have little importance. Probably they can be useful to professional bodybuilders in competition but, according to the article, the results on hypertrophy are trivial
3-Diet and sleep have smallish effect, maybe together they amount to more considerable effect on mTOR. Even here, there are good suggestions in Brad Schenfeld’s book. The muscle-building diet is based on a prevalence of carbs and protein, with a little fat.
But it is easy to reason that we could ignore the details of diet, sleep and supplements altogether, since the mechanical stress induced by resistance exercise appears to be such a large controlling variable of muscle hypertrophy.
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