January 27, 2024

Nutritional Biochemistry

New insights on maximizing protein utilization for muscle protein synthesis

A new study adds nuance – rather than contradictions – to conventional wisdom on protein intake patterns for maximal anabolic response

Peter Attia

Read Time 6 minutes

Dietary protein not only provides the necessary raw materials for building muscle, it also serves as an anabolic signal to temporarily ramp up muscle protein synthesis (MPS), particularly following resistance exercise. Previous research has indicated that ~20-30 grams of ingested protein may be sufficient to maximize MPS in the 2-3 hours following ingestion, and intake beyond this amount is thought to be burned (i.e., oxidized) as a fuel for the body. Thus, conventional wisdom holds that total daily protein intake ought to be distributed throughout the day into 3-5 meals, each with at least 20 grams of protein, in order to maximize the anabolic benefit of protein intake and sustain increased MPS over a longer period of time.

But last month, a study published in Cell Reports Medicine challenged this conventional advice, suggesting that anabolic responses might continue to increase in response to well over 20-30 g of protein ingestion. Many – including the study authors – have interpreted these data as upending the notion of an upper limit to the amount of protein from a single meal that can be utilized for MPS, yet when we look more closely, we find that, rather than negating previous beliefs about protein distribution, these new findings add an important layer of nuance to them.

A primer on protein metabolism

When we consume dietary protein, it is first broken down in the stomach and small intestine into its basic units, amino acids (AAs). AAs are then absorbed and can be transported via the bloodstream to various tissues throughout the body for use in protein synthesis (in addition to muscle protein synthesis mentioned above, protein synthesis also includes synthesis of critical enzymes and structural components present in every cell in the body).

The increase in circulating AA levels following protein ingestion serves as a signal to boost protein synthesis (i.e., anabolism) rates, yet dose-response studies suggest that these anabolic responses have an upper limit. Specifically, most studies have shown that 20-30 g of protein stimulates maximal protein synthesis in healthy adults, with no further increase with higher levels of protein intake. This implies that the body is not capable of utilizing more than ~30 grams of protein for anabolism at once, and since AAs – unlike fats and carbohydrates – cannot be stored by the body for later use, any excess ingested protein is thus oxidized for energy. To maximize utilization of protein for MPS or other anabolic processes (and minimize protein oxidation), dietary protein must therefore be ingested periodically throughout the day. However, given that many animal species do not adhere to such a distributed feeding pattern, researchers Trommelen et al. sought to put these limits to the test, investigating whether larger amounts of protein might indeed increase anabolic responses when assessed over longer post-ingestion periods than those assessed in most studies to date.

About the study

Trommelen et al. monitored AA dynamics in 36 healthy, active human participants (ages 18-40) using blood and muscle tissue samples collected over 12 hours after protein ingestion. Subjects were randomized to receive a 25-g protein solution (25PRO), 100-g protein solution (100PRO), or a placebo solution (0PRO) following a resistance exercise session, with protein solutions consisting of milk protein labeled with stable isotopes (carbon-13) at the amino acids phenylalanine and leucine in order to observe utilization of diet-derived protein. The investigators also used isotope-labeled AAs infused prior to exercise as a means of monitoring the effects of protein ingestion on endogenous protein dynamics.

They observed rapid elevations in circulating diet-derived (but not endogenous) AA levels following ingestion of either the 25-g or 100-g protein solution. The higher dose corresponded to a higher initial spike (within the first 2-3 hours post-ingestion) relative to the 25PRO group, as well as maintenance of higher levels throughout the full 12-hour post-ingestion period. This pattern was mirrored in the rate of AA uptake from circulation into tissues, which showed a dose-dependent early spike in the protein-treated groups, followed by a more modest but sustained elevation among the 100PRO group over the latter part of the 12-hour period.

Whole-body protein synthesis rates increased following ingestion of 25 g of protein and to a greater extent following ingestion of 100 g of protein – a pattern which also held for MPS specifically – and these responses were more sustained for the 100-g protein dose. Though the protein groups also experienced increased rates of AA oxidation post-ingestion (again, moreso in the 100PRO group), oxidation increases were very minor relative to protein synthesis increases, indicating that, contrary to expectations, only a small percentage of the 100-g protein solution was “wasted” as fuel instead of being used for protein synthesis. Because 100 g far exceeds the estimated threshold of 20-30 g for maximal protein synthesis, Trommelen et al. thus concluded that “the anabolic response to protein ingestion has no apparent upper limit in magnitude.”

Distributing absorption rather than intake

Results from this study also showed that AAs from ingested protein entered circulation very gradually, averaging a cumulative total at 4, 8, and 12 hours post-ingestion of 51%, 62%, and 66% of the 25-g dose and 26%, 44%, and 53% of the 100-g dose, respectively. The dietary AAs were likewise incorporated gradually into skeletal muscle, reaching a total of 18% (4.5 g) of the 25-g protein dose and 13% (13 g) of the 100-g protein dose by 12 hours post-ingestion. In other words, anabolic responses to protein ingestion were found to last for a far longer period of time than previously thought. But this extended duration also holds clues as to why these data seem to conflict with earlier work – and how to resolve the apparent contradiction.

The protein source in this study was bovine milk, in which most (~80%) protein is in the form of casein (the rest is whey). Digestion of casein and absorption of its AAs is an exceptionally slow process relative to other proteins, as casein forms insoluble curds in the acidic environment of the stomach and small intestine. By contrast, whey and many other protein sources are completely absorbed almost immediately – within an hour or two of ingestion. Trommelen et al.’s results align with these observations, as the spike in circulating AAs within the first two hours post-ingestion was likely attributed primarily to whey proteins, while continued elevations above baseline beyond this point were likely due to slower absorption of casein proteins. Indeed, the study data demonstrate that absorption of AAs in the 100PRO group was still ongoing even 12 hours after ingestion (see figure below).

Figure: Cumulative release of amino acids into circulation in the 12 hours following protein beverage ingestion at time 0. Black circles represent the 100PRO group and gray represent the 25PRO group. From Trommelen et al.

So in effect, this study did distribute protein, but did so by distributing absorption rather than distributing intake. The single doses of protein were effectively more of a constant trickle spread out over 12+ hours, such that, even following the 100-g dose, circulating AA levels at any given time never significantly exceeded peak levels previously reported for much lower doses (<40 g) of pure whey protein. Thus, the study did not test whether there is an upper limit to the anabolic response to the level of protein in circulation at any given time. Had Trommelen et al. used a more rapidly absorbed form of protein, such as the more commonly used whey protein, it’s possible that 100 g would have resulted in a plateau in MPS and a large spike in AA oxidation, in agreement with earlier research. (Indeed, the studies on which the 20-30 g threshold is based had generally used whey.)

“Slow proteins” can increase maximal anabolic responses 

And yet, even though these findings may not (as the authors contend) apply to all proteins across the spectrum of absorption rates, they nonetheless show that it is possible to sustain elevated MPS for at least 12 hours following a single protein meal – provided absorption rates are slow. In other words, these data indicate that slowing protein absorption can increase the maximum potential for protein utilization from a single meal by distributing the effects of that meal across a longer range of time.

This, in turn, means that choice of protein source impacts optimal protein distribution. For those getting protein mainly from whey, distributing intake over 3-5 meals of at least 20 g of protein each is still necessary for keeping up protein synthesis rates throughout the day and avoiding significant AA oxidation. But with protein sources that are absorbed more slowly, distributing total daily intake across one or two meals likely won’t compromise overall MPS and protein utilization. Casein is one of the most extreme examples of such “slow proteins,” but generally speaking, solid protein sources will be absorbed more slowly than protein powders and shakes, and because fiber typically impedes absorption, many plant-based proteins are also relatively slowly absorbed (a common exception being pea protein).

The notion that slower absorption can increase anabolic responses to protein ingestion has been raised in the past, and some prior research appears to support it. For instance, in a 2018 review, authors Brad Schoenfeld and Alan Aragon point to a study demonstrating that consumption of 70 g of protein in a single meal led to greater whole-body anabolic responses than 40 g of protein in a single meal when protein was in the form of beef patties in a mixed meal (i.e., including fats and carbohydrates in addition to protein) – a form that would be absorbed far more slowly than the pure whey used in many dose-response studies. As both 40 g and 70 g are outside the supposed dynamic range determined from whey studies, these results would suggest that the 20-30 g thresholds for protein synthesis can be increased dramatically by consumption of slow proteins or proteins in the context of a full meal.

A more detailed view of protein dynamics

The work by Trommelen et al. does not contradict conventional wisdom regarding protein utilization, but rather, it helps to provide valuable nuance. Although we can’t conclude from this study that anabolic responses to protein intake have no upper limit, the data reveal that “maximum” AA utilization for protein synthesis – as determined from earlier studies with whey protein – may be stretched depending on the form of protein consumed, potentially to a much higher ceiling than previously imagined.

I’ll soon be sitting down with one of the study authors, Dr. Luc van Loon, to discuss this paper on The Drive as part of a larger conversation on protein intake for training and health. Keep an eye out for that episode, as well as an upcoming premium newsletter in which our team will synthesize these findings with broader protein literature to explore in greater depth the practicalities of protein intake distribution and various protein sources, as well as amino acid composition and other considerations.


For a list of all previous weekly emails, click here

podcast | website | ama

Disclaimer: This blog is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this blog or materials linked from this blog is at the user's own risk. The content of this blog is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard, or delay in obtaining, medical advice for any medical condition they may have, and should seek the assistance of their health care professionals for any such conditions.
Facebook icon Twitter icon Instagram icon Pinterest icon Google+ icon YouTube icon LinkedIn icon Contact icon