Protein Wheysting?! No Significant Increase in PWO Protein Synthesis W/ 40g vs. 20g Whey, But 100% Higher Insulin, 340% More Urea & 52x Higher Oxidative Amino Acid "Loss"

No, I don't think the results would have been different, if the subjects had been young women. For older guys and gals, on the other hand, I am not 100% sure.
It has been a while since we've been taking a look at one of the two or three dozen "whey increases muscle protein synthesis" studies and, officially, we would have to wait not just for Santa, but actually until January 2014 to take a glimpse at the results Oliver C Witard, Sarah R Jackman, Leigh Breen, Kenneth Smith, Anna Selby, and Kevin D Tipton present in their soon-to-be-published paper in the journal of the American Society for Nutrition (Witard. 2014).

The intention of the researchers was (yet again) to "characterize the dose-response relation of postabsorptive rates of myofibrillar MPS to increasing amounts of whey protein at rest and after exercise in resistance-trained, young men", (Witard. 2014). This is nothing new, but still right up the average SuppVersity reader's alley, I suppose.

So what about the study design

The design of the study was simple. The 48 healthy volunteers consumed a standardized, high-protein
(0.54 g/kg body mass) breakfast. Three hours later, they all performed a standardized bout of unilateral exercise, consisting of 8x10 leg presses and leg extensions at 80% of their individual, predetermined one-repetition maximum. "Immediately" (max. 10min) after they were done with the leg workout the volunteers consumed
  • 0g, 10g, 20g, or 40g whey protein isolate
as a post-workout protein shake, of which I don't have to tell you that it was likewise... standardized, right! The subjects were then hooked up with the necessary instruments and tools to measure their
  • postabsorbtive rates of myofibrillar protein synthesis (MPS) , 
  • whole-body rates of phenylalanine oxidation and 
  • urea production 
over a 4-h period (the stopwatch started ticking the very moment the subjects had ingested the protein shake) in all four arms of this parallel research design, single-blind study with 7 subjects in each of the 0, 10, 20, and 40g whey protein isolate groups.
Change (%) in myofibrillar and sarcoplasmic protein synthesis after ingestion of 25g whey at rest (FED) and resistance exercise (FED-EX) after 3h and 5h (Moore. 2009a)
Just a reminder: You do remember that there is another muscular compartment where we can measure protein synthesis? Right? The sarcoplasma, i.e. the zone around the myofibers, where the satellite cells reside. At least for the exercised leg, in the study at hand, this may not be that important, though, because "in contrast [to protein feeding at rest], resistance exercise rapidly stimulates and sustains the synthesis of only the myofibrillar protein fraction after protein ingestion" (Moore. 2009; my emphasis). The word "only" is slightly misplaced. If you look at the figure on the left, it's obvious that "mainly" or "more significantly", would probably be more accurate.
Now that you know all the important details about the study design, it's almost time to take a look at the results. Before we finally do that, let's just briefly recapitulate the results of (Cuthbertson. 2005) who observed that 10 g EAAs at rest and (Moore. 2009b) who observed that 20 g egg protein after exercise were "optimal for the maximal stimulation of MPS in young adults". This is after all, what the researchers hypothesis that "20 g of whey protein (~10 g EAAs) would be sufficient for the maximal stimulation of myofibrillar-MPS rates at rest and after resistance exercise in trained, young men" (Witard. 2014) was based on.
Figure 1: Post-exercise serum insulin (AUC, µmol/ml x 4h) and leucine peak (mmol/ml), total phenylalanine oxidation (AUC µmol/ml x 4h x 100), urea production (AUC µmol x 4h) and plasma urea (AUC mmol/l x 4h), as well as myofibrillar protein synthesis (MPS) in the 4h after the workout (Witard. 2014).
As you can see, the actual study results confirm the scientists suspicion: The 20g of whey protein did maximized the myofibrillar protein synthetic response to a hypertophy-oriented leg training workout (see bottom line for an explanation of why I chose to underline the word "leg") in rested and exercised muscle of ~80-kg resistance-trained, young men.
We are talking about statistical significance here: I know what you are going to tell me, now. And yes, you are right. The protein synthesis was in fact higher, but that's more of a matter of how sustained the increase was and not a matter of a "faster" protein synthesis. In other words, with 20g of a fast absorbing whey protein and a whole meal with slow absorbing proteins 30-40min after you will achieve the same - if not higher muscle protein synthesis rates in the long(er) run (>2h)... ah, and by the way: The response in the untrained leg confirms: There is not additional MPS stimulus from 40g vs. 20g of whey (much contrary to the insulin spike, by the way ;-).
The side-finding that this in medical terms "high" amount of whey also lead to significant increases in urea production is - at least in my humble opinion not surprising. The increased ammonia production due to higher protein oxidation rates does after all have to be cleared from the body. Against the background that this process is facilitated by the urea cycle, anything but the observed increase in urea production would have been startling.

"Confirmed: All Wheys, Not Just Hydro Whey Boost Glucose Uptake and Liver + Muscle Glycogen Supercompensation. Plus: How Can Taurine help?" | more
The fact that this increase in urea production and plasma concentrations did occur in the first place, on the other hand, is a clear cut sign for the onset of "wastefulness" with higher protein consumption - or as Selby et al. put it:
"Indeed, in the current study, urea production rates , as well as plasma urea concentrations, were markedly raised with the ingestion of 40 g protein.

Thus, instead of incorporation into muscle protein, the metabolic fate of excess exogenous amino acids contained in the 40WP was predominantly the oxidation or excretion as an indication that a state of amino acid excess was reached." (Selby. 2014)
Whether you consider this a "waste" of valuable dietary protein or not is probably a matter of your personal concept of protein nutrition.

If you are on the "protein worshipper" side of the devide, you will probably argue that you better "burn" protein for energy than carbs or fats, because otherwise you would have to eat less protein and  more carbohydrates + fat and would "become fat". It goes without saying that this is bullshit - not to mention that anyone who is interested in performance and the sanity of his doctor. The poor guy would freak out, when he'd see the elevated AST and ALT levels the combination of "protein only" diets + intense physical exercise are going to produce.

Your doctor's mental sanity or the excited calls of his receptionist are probably not really your concern, but I would still not discard the performance and, in the long run, metabolic and psychological detriments from running on protein only. From an (bio-)energetic perspective it's the least effective of the three macronutrients and thus not exactly a suitable fuel source for high performance athletes.
"So what would you put into a post-workout shake, Adel?" Personally, I have ~30g of whey protein and some fruit, like 1-2 bananas, a ton of water melon, or whatever else I have lying around. If no fresh fruit is available, I just grab some instant oats. And while I know that the carbs won't help with protein synthesis (Koopman. 2007), there is hardly any better timepoint to use the massive isulin spike and shuttle the glucose into the muscle than after the workout (van Loon. 2000). For me personally, the addition of carbs also prevents the brainfog, I get due to low blood sugar after an intense leg-workout and a protein shake without carbs. So, if you feel like you're not thinking straight or would have to go to bed after your shake, I would try to fix that by adding some carbs to the equation.
Bottom line: With the study at hand we (will) get further confirmation of the existence of a protein threshold of ~20g of whey protein, beyond which we won't see additional increases in acute myofibrillar protein synthesis after having a high protein breakfast and the completion of a standardized hypertrophy-oriented leg workout in young, healthy, male individuals.

If you wonder about the many underlined words in this conclusion, I may remind you of the fact that all these words describe boundary conditions that won't be fulfilled for everyone: There are more than enough people who don't have a high protein breakfast. There are people who train their whole body in a single session and would thus upregulate the protein synthesis in more than just the leg muscles. Not everyone is still young (and there is albeit inconclusive evidence that older individuals need more protein). For long-term muscle gains the sarcoplasmic protein synthesis may and the long-term (not acute) net protein balance definitely is more important than the acute increase... I could go on, but I guess you see, where this is heading: Theoretically, we'd have to do another 100 studies, but I am not sure whether Glaxosmith Kline who support Tiptons research would want to finance all of these ;-)

  • Cuthbertson, D., Smith, K., Babraj, J., Leese, G., Waddell, T., Atherton, P., ... & Rennie, M. J. (2005). Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. The FASEB journal, 19(3), 422-424.
  • Koopman, R., Beelen, M., Stellingwerff, T., Pennings, B., Saris, W. H., Kies, A. K., ... & Van Loon, L. J. (2007). Coingestion of carbohydrate with protein does not further augment postexercise muscle protein synthesis. American Journal of Physiology-Endocrinology And Metabolism, 293(3), E833-E842.
  • Moore, D. R., Tang, J. E., Burd, N. A., Rerecich, T., Tarnopolsky, M. A., & Phillips, S. M. (2009a). Differential stimulation of myofibrillar and sarcoplasmic protein synthesis with protein ingestion at rest and after resistance exercise. The Journal of physiology, 587(4), 897-904.
  • Moore, D. R., Robinson, M. J., Fry, J. L., Tang, J. E., Glover, E. I., Wilkinson, S. B., ... & Phillips, S. M. (2009b). Ingested protein dose response of muscle and albumin protein synthesis after resistance exercise in young men. The American journal of clinical nutrition, 89(1), 161-168.
  • van Loon, L. J., Saris, W. H., Kruijshoop, M., & Wagenmakers, A. J. (2000). Maximizing postexercise muscle glycogen synthesis: carbohydrate supplementation and the application of amino acid or protein hydrolysate mixtures. The American journal of clinical nutrition, 72(1), 106-111.
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