L‑Alanylglutamine Blunts Allegedly Catabolic Signaling Proteins After Exercise - Does This Mean Sustamine™ is a Potent Anti-Catabolic Agent We All Should be Using?

Can a few grams of Sustamine™, i.e. L‑Alanylglutamine, prevent protein breakdown after an intense workout? How significant are reduced AMPK and NF-kB protein levels? And lastly: Do we even care about 20 min? 
Glutamine dipeptides such as l-alanylglutamine (AlaGln) have been designed to improve upon the low solubility and stability of regular l-glutamine and are used in more and more sports drinks and health products. Maybe you have even used one of them without knowing? Just take a look at the labels. Does any of your "proprietary blends" contain Sustamine™? Yes? I am by no means surprised.

Due to its increased stability and correspondingly higher absorption rates for intact glutamine, AlaGln dipeptide facilitate greater increases in plasma glutamine concentration compared with glutamine or wheat protein, which has the highest glutamine content of all common protein formulas (Harris. 2012; Rogero. 2006).
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Cruzat et al. report in their 2010 study that AlaGln administration can attenuate muscle damage, but their results are based exclusively on the observation of lower inflammation biomarkers following prolonged endurance exercise (Cruzat et al. 2010). A more significant outcome parameter was measured recently by Wang et al. (2015). In their study, the scientists investigated
"the effects of acute Sustamine™ (SUS) supplementation, a dipeptide composed of alanine and glutamine, on the signaling pathways controlling MPS and MPB post resistance exercise. Comparisons were made relative to whey protein (WP) supplementation" (Wang. 2015).
In that it is a bit disappointing that the subjects" of the study were eighty-nine male Sprague–Dawley rats who had been familiarized with the standardized exercise protocol, before they had to do latter climbing 10 times with a weight equal to 75 % of their body mass attached at the base of the tail.
Figure 1: Levels of the alleged markers of protein breakdown, NF-kB, AMPK and FOXO3A, 20 min (A) and 40 min (B) after the workout (Wang. 2015).
Before the exercise trial, the rats had been fasted, afterwards, blood was collected before the rats received either (1) whey protein (WP = 0.4 g/kg), (2) a low dose of Sustamine™ [LSUS = 0.1 g/kg, l-alanylglutamine (AlaGln); Kyowa Hakko Bio. Ltd., New York, NY], a high dose of Sustamine™ (HSUS = 0.5 g/kg), or placebo (PLA = 0.52 g/kg glycine, isonitrogenous to the HSUS) by intubation.  The results of the extensive testing the scientists conducted on their hairy subjects indicate that (Wang. 2015):
  • Figure 2: Unfortunately, Wang et al. forget that NF-kB is only "bad" for your muscle if it's chronically elevated (Kramer. 2007)
    All supplements elevated the phosphorylation of FOXO3A above SED at 20 min post exercise, but only the SUS supplements significantly reduced the phosphorylation of AMPK and NF-kB p65. 
  • SUS supplements had no effect on mTOR signaling, but WP supplementation yielded a greater phosphorylation of mTOR p70S6k, and rpS6 compared with PLA at 20 min post exercise. 
  • By 40 min post exercise, phosphorylation of mTOR and rpS6 in PLA had risen to levels not different than WP. 
At first sight, it may thus in fact seem as if "SUS blocks the activation of intracellular signals for MPB [muscle protein breakdown], whereas WP accelerates mRNA translation" (Wang. 2015). Upon closer scrutiny of the results it does yet turn out that exercise-induced increases in AMPK are not only highly transient (please don't fall for the common bullsh*t concept that you could "lose muscle" over the 20 minutes where AMPK is higher in the WP and PLA group), but also not necessarily catabolic (I have discussed this at length in a previous article and won't repeat the whole sermon here | learn more). Rather than an inhibition of protein breakdown, the decrease in AMPK may rather trigger reduction in fat oxidation and glucose uptake both of which are elevated by AMPK - an effect you probably don't expect from a useful dietary supplement.
Figure 3: I am not sure, but personally I would say that the reduced mTOR response in the low dose Sustamine™ group may actually be the most significant result of the study at hand. After all, most supplements contain less than the 1.3g of this patented and thus expensive agent that would be the human equivalent of the 0.1g/kg used in the LSUS group.
So what about NF-kB is that irrelevant, as well? While the change in NF-kB is likewise transient, it is undebatable that NF-kB is involved in skeletal muscle atrophy (Li. 2008). To think of NF-kB as a merely proteolytic would yet be short-sighted, because it is also involved in the adaptational process to exercise. As the figure from Kramer et al. shows, only chronic elevations of NF-kB are truly catabolic. Transient elevations of NF-kB on the other hand are a motor of "improved fuel homestasis, increased antioxidant capacity, tissue regeneration" and thus all the "beneficial physiolog[ical]" (Kramer. 2007) effects of exercise training.

The fact that FOX-O, another protein that's involved in the breakdown of muscle protein (Sandri. 2004), isn't decreased by Sustamine™ either, I  personally do have my doubts that the alleged anti-catabolic effects Wang et al. believe to have observed are practically relevant. But hey, maybe Kyowa Hakko Bio Co who were paying for the study at hand want to sponsor a study with a more relevant study design to prove that one of their best-sellers is actually worth spending money on ;-) | Comment on Facebook!
References: 
  • Kramer, Henning F., and Laurie J. Goodyear. "Exercise, MAPK, and NF-κB signaling in skeletal muscle." Journal of Applied Physiology 103.1 (2007): 388-395.
  • Li, Hong, Shweta Malhotra, and Ashok Kumar. "Nuclear factor-kappa B signaling in skeletal muscle atrophy." Journal of molecular medicine 86.10 (2008): 1113-1126.
  • Sandri, Marco, et al. "Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy." Cell 117.3 (2004): 399-412.
  • Wang, Wanyi, et al. "l-Alanylglutamine inhibits signaling proteins that activate protein degradation, but does not affect proteins that activate protein synthesis after an acute resistance exercise." Amino acids (2015): 1-10.
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