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mTOR: David Sabatini on stemtalk


mccoy
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A new, excellent stemtalk interview to the eminent cellular biologist David Sabatini, the one who discovered the mTOR pathway.

Some myths are shattered by this interview. In particular,:

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00:42:27] Ken mentions that protein intake and downstream mTOR activation is often said to be associated with dysregulated cell growth (i.e. cancer). He goes on to ask if there is there sufficient evidence to suggest that high levels of protein or amino acid intake are necessary or sufficient to produce clinically-meaningful cancers?

Sabatini answers: there is no evidence at all. If we feed an excess of amminoacids to the system, mTOR activity will reach a maximum threshold and the excess nutrients will be excreted. The max threshold is not such to cause cancer, whereas mutation of GTpases, the intermediate sensing protein, may take mTOR activity to pathological high levels such as to cause cancer.

So, the high quantities of protein eaten by Atkins dieters or by bodybuilders would jconstitute a simple waste and just be excreted. 

Whereas the benefits of calorie restriction and methionine restriction are probably, according to Sabatini, related to the triggering of autophagy. by mTOR inhibition and the subsequent homecleaning. Excess fo autophagy can be very detrimental in that when the last cellular ribosome and mytocondia are digested there is a point of no return, cellular functions are lost.

Another very interesting issue: the insulin signal governs mTOR in skeletal muscles, the nutrients signal governs liver mTOR.

Actually, some competitive bodybuilders will inject themselves with insuline to amplify muscle growth. Literature says otherwise but Sabatini is a candidate to the Nobel prize and the one who knows most about mTOR.

Some of  the above prompted a readjustment of my conceptual model of  mTOR, such as:

  • Role of carbs (energy substrate) in muscle growth, their 'fueling' the proteins would mean fueling the insulin signal which activates mTOR  in such a way  to maximize protein efficiency. In a few words the belief that not so many protein are needed in the presence of significant carbs would be supported by Sabatini
  • More protein would be useful only insofar as they feed the insulin signal directly and by gluconeogenesis (eating more protein while dieting or cutting notoriously spares loss of muscle tissue). 
  • Carbs optimization rather than protein optimization would be needed to promote muscle growth (I remember Sergio Oliva, historical winner of 3 Mr Olympia, suggesting fresh fruit to increase in muscle mass)
  • Keto diets good to loose weight but also cause loose of muscle mass (as testified by bodybuilders), because of substantial drop in the insulin signal. Low carb-Low protein classic keto diet especially causes a decrease in muscle mass, since the insulin signal is killed by very littel glucose and very little protein (which also stimulates insulin plus cannot activate in this case gluconeogenesis due to the low amounts). The Rosedale diet is an example of this. I've followed that for a couple of months, notwithstnding exercise I lost muscle mass AND adipose tissue.

By this conceptual model, Valter Longo's suggestion to moderate protein would not be so meaningful, barring the avoidance of other detrimental effects (such as inflammation, which is probably a real one, especially with animal protein).

Valter Longo's longevity diet would not have huge effects aside the ones coming from a healthy diet with a low glycaemic index and moderate nutrients. Whereas the FMD would promote autophagy by the substantial decrease in the insulin +protein signals.

 

 

 

 

Edited by mccoy
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I'm searching now some  bodybuilders' sites on the anabolic effect of insulin, which is very well known. It turns out that some form of insuline optimization is suggested, by timing the consumption of carbs aroudn workouts. Sort of pre and post workout meals made up of carbs instead than protein.

https://www.t-nation.com/diet-fat-loss/insulin-advantage

 

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Allow me to quote Guyton and Hall's Textbook of Medical Physiology:

"In some unexplained way, insulin 'turns on' the ribosomal machinery. In the absence of insulin, the ribosomes simply stop working, almost as if insulin operates an 'on-off' mechanism."

So does this mean that insulin "helps" build muscle? No, it means that insulin is required to build muscle.

Actually, we very well know that insulin is a powerful signal which activates mTOr (via the PIK3-akt path) in muscle tissues. So it really operates the on-off mTOR masterswitch.

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nsulin actively transports certain amino acids directly into the muscle cells. You can probably guess which amino acids get this special treatment. BCAAs – which are packed in workout nutrition for a reason.

This has been stated by Sabatini, insulin mediates the transport of nutrients into the cell (glucose and AAs).

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Want to gain muscle faster? Increase the amount of insulin you secrete. This is especially beneficial to do around weight training. Insulin will not convert glucose to fat if it can first store it as muscle glycogen.

And after an intense weight-training session, both muscle and liver glycogen are depleted and ready to soak up serious glucose. So, don't be shy with the carbs at this time.

For even faster muscle gain you should also boost insulin levels another time or two throughout the day. You could accomplish this with a couple more carb-containing meals.

Then, in order to cover the fat loss part of this equation, keep insulin levels low during the remainder of the day.

There is no practical scheme suggestes though to follow the above. "boost insulin levels another time or twwo troughout the day". How and how much?

"keep insulin low during the reminder of the day". This is easier, do not snack on carbs especially simple carbs, but the insulin peak may linger after the preceding meal...

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FWIW:

Exercise and the Regulation of Skeletal Muscle Hypertrophy

https://www.researchgate.net/publication/286053571_Exercise_and_the_Regulation_of_Skeletal_Muscle_Hypertrophy

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[...]neither IGF1 receptor phosphorylation nor any other marker of receptor tyrosine kinase activation is increased following resistance exercise in rodents,25 suggesting that paracrine-related growth factors are not released in sufficient quantities to impact receptor function.

Notwithstanding the fundamental differences between rodents and humans,26,27 it is also important to point out that whereas insulin can induce phosphorylation of the IGF1 receptor, resistance exercise does not.25 Moreover, there is now significant data in human models to show that physiological increases in insulin concentrations, corresponding to those seen with ingestion of a meal, play a permissive, and not a stimulatory role in the regulation of MPS.28,29

 

Edited by Sibiriak
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Mccoy:   By this conceptual model, Valter Longo's suggestion to moderate protein would not be so meaningful, barring the avoidance of other detrimental effects (such as inflammation, which is probably a real one, especially with animal protein).

While conceptual models are no doubt critical,  Valter Longo would surely point out the necessity of basing any practical longevity program on a much broader  epistemological foundation,  such as outlined in his "Five Pillars of Longevity".    These epistemological sources include basic research, complex systems studies,  animal studies, epidemiology, clinical studies, and centenarian studies.  All of them must be taken into consideration together when attempting to evaluate any practical recommendations.

 

 

Edited by Sibiriak
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Sibiriak, I have yet to delve into insulin and mTOR in MPS, but it may well be that Sabatini was referring to in vitro MPS, whereas in vivo and in humans only supraphysiological concentrations of insulin seem to  boost MPS. My intention is to search further details.

Re. Valter Longo, I agree that his model is multifactorial and the exam of a single factor is not significant in the context. This bestows to the 5 pillars model an high degree of reliability. Also, as far as I understood, he has been reasoning a lot about his model and asked opinions to specific experts in areas, like exercise, which are a little outside his arena. This does not mean that his model is necessarily bulletproof. Some weak points may be found, like the post-workout meal reccomandation which does not constitute and addition to the total daily proteic quota. I'm not sure but then we may miss some raw material for MPS, IF the RDA is not already higher than our basic+additional requirements. If the RDA is the benchmark, then the RDA+ a delta-protein should be according to logic advised.  I believe that there are other weaknesses in Longo's dietary suggestions, but as a whole they are most probably minor, it remains a formidable benchmark in practical longevity. 

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7 hours ago, Sibiriak said:

That's an excellent and exhaustive article, which sheds some light on some statements which seemed contradictory to me.

First of all, it has been observed that exercise induced elevations in IGF-1, growth hormone and testosterone do not impact significantly on MPS. We are speaking of physiological doses though, so the higher (supraphysiological) dosages used by some bodybuilders constitute a totally different ballpark.

Also, the role of hormones in RE-induced MPS is negligible, but the role of the same hormones in MPS  seems to be significant. That is, hormones seem to increase muslce mass independent of resistance exercise. They just  increase the baseline muscle mass upon which RE builds yet more mass.

The article also gives a name to the mechanoreceptors apparently responsible of mTORC stimulation in skeletal muscle: the FAK, or focal adhesion kinase protein.

This article probably deserves a thread on its own.

 

Edited by mccoy
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Mccoy: This does not mean that his [Longo's]  model is necessarily bulletproof.

I agree completely. 

My main point is this:  let's say you propose a possible health/longevity  program that involves high volume bodybuilding -style muscle hypertrophy training + high protein intake + vegan diet (or whatever).

Can such a program now or in the future be convincingly backed  by a full gamut of evidence from animal studies,  epidemiological studies,  cohort studies,  centenarian studies  and clinical trials in addition to a plausible mechanistic conceptual model?

 

 

 

Edited by Sibiriak
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5 hours ago, Sibiriak said:

I agree completely. 

My main point is this:  let's say you propose a possible health/longevity  program that involves high volume bodybuilding -style muscle hypertrophy training + high protein intake + vegan diet (or whatever).

Can such a program now or in the future be convincingly backed  by a full gamut of evidence from animal studies,  epidemiological studies,  cohort studies,  centenarian studies  and clinical trials in addition to a plausible mechanistic conceptual model?

I would say that's almost an impossibility! 

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The recent podcast episode with Peter Attia and Robert Lustig underlines an aspect related to insulin which is related to the above:

 

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  • Muscles don’t need insulin to import glucose: if they did then every diabetic would be paralyzed
  • The reason insulin works at the muscle is to import amino acids: for muscle growth, but not for muscle metabolism’

The 2nd point is maybe what Sabatini meant by insulin being the main signal for muscle growth. We also discussed previously the rise in blood insuline subsequent to purely proteic meals. In this context, glucose would not be needed at all (except in enough amounts not to activate AMPK). Bodybuilders' SOP dictate that a post workout protein meal should be accompanied by some glucose/carbs. Soem articles underline that carbs are not necessary to stimulate muscle growth.

The 1st point I don't know how to interpret, it should have perhaps specified Type 1 diabetics. I thought insulin activated the GLUT receptors to import glucose into muscle cells.

 

 

Edited by mccoy
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