Is there such a thing as a “muscle full” effect ?


The muscle full hypothesis was proposed by Atherton et al. based on their research from 2010 with an oral dose of 48g of whey protein (1) and older research by their group using continuous infusion of amino acids (2) and suggests that muscle protein synthesis is attenuated after time, and eventually returns to baseline, despite continuous availability of amino acids in circulation. It seems to concur with other research demonstrating a cap on muscle protein synthesis at a dose of around 20g of a fast digesting high quality protein, orally ingested (3,4). The Atherton study was a milestone, but it has since led to rather poorly designed research (5) claiming that eating too frequently would impede muscular gains, which is simply not the case. We will discuss that study at length toward the end of the article. First I think it is perhaps important to discuss the biochemical basis for the muscle full effect and the Atherton study itself.

The biochemistry of nutrient driven muscle protein synthesis

You can find more detailed descriptions of the process of mTORC1 activation, its upstream regulators and its downstream effectors, in this article. We will only briefly re-iterate the relevant topics here. Suffice it to say that when sufficient insulin or growth factor signaling is present (insulin levels of 20-30 mU/L or higher, or exercise induced IGF-1 signaling) amino acids, with a key role for leucine, stimulate the activity of the mTOR complex 1 (mTORC1), the cells key anabolic signal integrator, which is considered both necessary and sufficient for muscular hypertrophy. That implies that overexpression of mTORC1 in an otherwise normal cell leads to anabolic events, and that blocking of mTORC1 leads to attenuation of growth. How amino acids achieve this is a complex and (despite making a lot of headway in recent years) still not completely understood process, but it begins with the entry of leucine and other amino acids into the cell. Leucine is taken up by the SLC7A5/SLC3A2 (which I have affectionately dubbed the “leucine pump” for easy reference) transmembrane protein, but the process requires the expulsion of glutamine from the cell. Indeed, research has demonstrated that in cells that cannot manufacture glutamine readily that glutamine deprivation blocks mTORC1 signaling because the cell cannot absorb leucine (6). When leucine concentrations in the extracellular space rise, glutamine is pumped out the cell and exchanged for leucine, which is taken up into the cell. Once in the cell, leucine stimulates glutaminolysis, the two-step process of turning glutamine into alpha-ketoglutarate (alphaKG). AlphaKG may actually play a direct role in mTORC1 activation (7), although that hasn’t been fully confirmed. In any case it forms the substrate for at least two other non-essential amino acids (proline and arginine) that will likely be required for muscle protein synthesis. At the same time the high nitrogenous medium, due to the presence of a lot of amino acids, inhibits Glutamine synthesis, the reverse process of making glutamine out of alphaKG (8). Through this three pronged approach, and the lowering of extracellular leucine,  leucine uptake depletes the cell of glutamine which forms a negative feedback on its own absorption. Since the amino acids stimulate muscle protein synthesis, which incorporates them into proteins, their level inside the cell drops, which then takes the brakes off glutamine synthesis increasing intracellular glutamine, provided energy is still high enough. This is a key factor because extra alpha-KG is obtained as a sub step of the Krebs cycle, but only if the cycle is halted at that phase, and high levels of ATP are a requirement for that inhibition.

This fits perfectly logically in the aforementioned studies in the intro of their being a ceiling on protein intake at any given time, and the amount of muscle protein synthesis it can produce. It also makes sense in the real world, since no one ever got muscular just sitting around and eating. The primary use of nutrient-driven MPS is to replace existing protein, not to result in their increased accrual. As was discussed at length in previous articles, said dose was established in a vacuum with a fast-digesting high quality protein, and is logically influenced by exercise, lean bodyweight (the more muscle, the more amino acids are required for them all to reach muscle full status), age and the type of food (since digestion time spreads protein out over time, reducing the dose at any given time). However, the Atherton study, for the first time demonstrated some interesting things.

What we learned from the Atherton study

The key discussion point from the research of Atherton et al. was that they noticed that the fractional synthetic rate tapered off BEFORE the signaling molecules associated with muscle protein synthesis did (in this case the downstream effectors of mTORC1 : S6K1, 4E-BP1 and eIF4G). The researchers proposed there would be a mechanism that gauges the cells capacity for protein synthesis. This mechanism may actually have been evident from the data in the study itself, since both insulin levels and phosphorylation state of its downstream effector Protein Kinase B (Akt) mirrored the fractional synthetic rate perfectly. It would make sense in the energy-depleted state (the subjects reported for the test fasted) that in the absence of an overriding insulin signal, despite part of the machinery still being operational, the breaks were being put on the muscle protein synthesis. The data outlines are almost too perfect for that not to be the case, and further research should be carried out to elucidate the matter. The researchers also noted absolutely no difference in phosphorylation on Ser2448 on mTORC1, ERK1/2 or AMPK compared to the post-absorbtive (fasted) values. AMPK phosphorylation levels in that state would have been significant, due to the fasted state of the subjects, and that likely reduced Ser2448 phopshorylation. Likewise, no exercise was performed in the previous 72 hours, also a known factor in Ser2448 phosphorylation. These are rather clear indications that signaling was not maximal or even optimal. Also the slight trend for FSR to rebound after dephosphorylation of key signaling molecules seems to indicate some rebound.

It therefor seems likely if a similar trial was conducted in a fed state, sometime after exercise we would have observed full mTORC1 phosphorylation, a decrease in AMPK phosphorylation and MPS values mirroring those of the signaling molecules because the necessary pieces would be in place to continue supporting the FSR. Since we know insulin and glucose don’t directly affect MPS, I really don’t see any issue with conducting studies in a fed state, as opposed the longstanding premise to conduct all these studies in the unrealistic fasted state. It is a possible confounding factor, but so is a lack of energy, as this will never occur in an athlete attempting to gain muscle. And if need be, a preliminary study could chart the differences between a fed and fasted group. The insistence on fasting is archaic, unrealistic, and often one of the factors most likely to obscure possible effects, as we will see in the discussion of the Areta et al. study (5).

What we (didn’t) learn(ed) from the Areta study

This study, from the renowned Stuart M Phillips research group, is one I was actually looking forward to, because I had already learned they were coming out with new research on protein spread that demonstrated eating every 3 hours, rather than every 1.5 hours or every 6 hours, was considerably better in regards to muscle protein synthesis. To me that was a bit of a foregone conclusion, considering what we knew about needing threshold levels of amino acids to maximally stimulate MPS (9), and the benefit of extending time spent in hyperaminoacidemia (10) for maximal muscle accrual. However, the researchers tried to explain the lesser effects of their pulse (feeding every 1.5h) group by way of the “muscle full”-effect, and their bolus (every 6h) group simply by the fact that above the 20g mark, extra amino acids would be terminally oxidated. The faulty conclusions aside, the setup of the whole study was dismal because the subjects reported in a fasted state (yet again) and were not given anything to eat that entire day EXCEPT for the 80g of protein divided in 8x10g, 4x20g or 2x40g doses. The number of problems associated with this is infinite. Again, the fasted state, as well as the hypocaloric conditions (320 kcal for a whole day ?) would seriously impede maximal signaling in ALL of the groups. In this study resistance exercise, though very limited, was performed, and indeed, unlike the Atherton study, Ser2448 phosphorylation was detected, and it remained the same at all timepoints in all groups, demonstrating that it isn’t linked to protein feeding per se (or at least not in hypocaloric low energy conditions). The Ser2448 phosphorylation may therefore be a crucial element in how resistance exercise synergistically enhances MPS for periods up to 48h (11). Next up is the clear variables caused by the feeding pattern itself.

When a group consumes 4 doses at 0, 3, 6 and 12 hours and a group consumes 8 doses at 0, 1.5, 3 etc hours, your measurement at 6h will be for 40g in the 4×20 group, but only for 30g total in the 8×10 group. That alone causes a disparity in the results. But more importantly, the dose to maximally stimulate protein synthesis in one sitting is 20g of whey, with whey digesting over about 2h. That means you would have passed nearly half the day before the 8×10 group even once reaches that cumulative level, while the 4×20 group reaches it at every feeding. This is evident from the increasing trend in the line for all the data in the pulse (8×10) group. So you have a hypocaloric, fasted group that is given a dose that is half of optimal and continuously behind on its total protein intake throughout the measured period, right up to the 10.30h mark, then it seems logical, without even conducting a study and wasting someone’s money, that the cumulative MPS for various timepoints is going to be a LOT lower, doesn’t it ?

This study could have easily been conducted in a fed (anything but protein obviously) state, with a proper resistance training protocol and using twice the dosage of whey in the protocols. If you postulate (since none of the data necessarily corroborates it, it remains hypothesis regardless of setup) that anything above 20 will be terminally oxidized, then there should be no qualms about doing the study with 8×20, 4×40 and 2x80g respectively, so that each dose at least has maximal stimulation at any given measured timepoint. That would make the cumulative data a lot more reliable. In short, I was extremely disappointed with a study I had been anticipating, and given the concept it had a lot more promise. Having read a great deal of these studies, it seems to me that many of them are based off of each other’s hypothesis’ without corroborating the findings, understanding the molecular basis of the events or exploring other options, which steers the outcome in a certain direction and turns them into a bit of a self-fulfilling prophecy rather than actual research. As I stated, I could have predicted the outcome of this study design and given you the reasons why without even conducting it. It makes little sense to me that a whole research group failed to see the shortcomings in this.


Well I’m still sticking to my guns based on previous research that the outcome of this study is correct, that an intermediate (6-7 feedings per day) feeding pattern is better suited for muscle accrual, based on the data that not only says there is a ceiling to protein that can be used in one sitting (3,4), but also data showing that extending time spent in hyperaminoacidemia by just a few hours can notably increase muscle mass accrual over just a few weeks (10), than bolus (3 squares a day) feeding. I likewise agree it is better than a pulse pattern for most people because of research showing that a threshold level of amino acids must be reached for MPS to become optimal, and a certain dose for it to be maximal. In other words, it is counter-productive, as in the Areta study design, to spread your protein thinner than when meals provide the equivalent of the ceiling dose (dependent on rate of digestion, quality of protein etc).

In practical terms that means it’s perfectly ok to have more than 6-7 meals a day if so required (because for instance you need more calories and cannot ingest more in the allotted 6 sittings), provided that each meal provides a minimum amount of protein (around 10-15g per hour depending on bodyweight), but also that for most people there is simply no REQUIREMENT to eat more often than 6-7 meals a day. There is however more than sufficient data to suggest that eating at least every 3-4 hours, even if not necessary for caloric reasons, is more beneficial for muscle gains, because it helps maintain a higher level of hyperaminoacidemia throughout the day.


References :
  1. Atherton PJ, Etheridge T, Watt PW, Wilkinson D, Selby A, Rankin D, Smith K, Rennie MJ. Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling. Am J Clin Nutr. 2010 Nov;92(5):1080-8.
  2. Bohé J, Low JF, Wolfe RR, Rennie MJ. Latency and duration of stimulation of human muscle protein synthesis during continuous infusion of amino acids. J Physiol. 2001 Apr 15;532(Pt 2):575-9.
  3. Moore DR, Robinson MJ, Fry JL, Tang JE, Glover EI, Wilkinson SB, Prior T, Tarnopolsky MA, Phillips SM. Ingested protein dose response of muscle and albumin protein synthesis after resistance exercise in young men. Am J Clin Nutr. 2009 Jan;89(1):161-8.
  4. Dideriksen K, Reitelseder S, Holm L. Influence of amino acids, dietary protein, and physical activity on muscle mass development in humans. Nutrients. 2013 Mar 13;5(3):852-76.
  5. Areta JL, Burke LM, Ross ML, Camera DM, West DW, Broad EM, Jeacocke NA, Moore DR, Stellingwerff T, Phillips SM, Hawley J, Coffey VG. Timing and distribution of protein ingestion during prolonged recovery from resistance exercise alters myofibrillar protein synthesis. J Physiol. 2013 Mar 4.
  6. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO.Bidirectional transport of amino acids regulates mTOR and autophagy.Cell. 2009 Feb 6;136(3):521-34.
  7. Durán RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E, Hall MN.Glutaminolysis activates Rag-mTORC1 signaling.Mol Cell. 2012 Aug 10;47(3):349-58.
  8. Purich DL. Advances in the enzymology of glutamine synthesis. Adv Enzymol Relat Areas Mol Biol. 1998;72:9-42.
  9. Dardevet D, Rémond D, Peyron MA, Papet I, Savary-Auzeloux I, Mosoni L. Muscle Wasting and Resistance of Muscle Anabolism: The “Anabolic Threshold Concept” for Adapted Nutritional Strategies during Sarcopenia. ScientificWorldJournal. 2012;2012:269531.
  10. urk A, Timpmann S, Medijainen L, Vähi M, Oöpik V. Time-divided ingestion pattern of casein-based protein supplement stimulates an increase in fat-free body mass during resistance training in young untrained men. Nutr Res. 2009 Jun;29(6):405-13.
  11. Phillips SM, Tipton KD, Aarsland A, Wolf SE, Wolfe RR. Mixed muscle protein synthesis and breakdown after resistance exercise in humans. Am J Physiol. 1997 Jul;273(1 Pt 1):E99-107.


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