Thursday, November 17, 2016

Glycine for Your Gains? Glycine Boosts Protein Synthesis (80%), Reduces Protein Degradation (-30%) in Muscle Cells

If glycine worked in athletes as it did in pigs or even isolated muscle cells, in which scientists recently observed a dose-dependent increase in protein synthesis (up to 80%) and reductions in protein degradation (-30%), it would be a go-to supplement for dieting athletes.
Glycine is not exactly the most popular amino acid supplement in the health and fitness community. With recent studies by a group of Chinese and American scientists from the State Key Laboratory of Animal Nutrition in China and the Texas A&M University, this may change - rightly so?

Only recently Wang et al. were able to show that dietary glycine supplementation enhances skeletal muscle growth in young pigs (Wang. 2014a,b) - an excellent model of human metabolism. In view of the fact that the mechanism has hitherto not been fully understood, it was difficult to judge whether the smallest possible amino, i.e. glycine, could / would be useful for trainees as well.
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With their latest study, the same team of scientists, this time with KaiJi Sun as their lead author (Sun. 2016), provide an experimentally supported explanation of the anabolic effects of glycine - an explanation that is not just convincing but would also suggest that glycine could be an interesting supplement for bodybuilders and fitness freaks, as well as their grandparents.
Table 1: Physiological functions of glycine in animals and humans (Wang. 2013).
How's that? Well, while we are dealing with a cell line study, the scientists' analysis I'd like to remind all of you who are about to click on "comment" and complain that this is a follow-up study on the muscle-specific effects of an amino acid of which we have known for quite long that it is important for animal and human health.
Where's the human study in trained athletes? Early evidence for its ergogenic effects comes from Buchman, et al. (1999) who actually wanted to use glycine as a control for the beneficial effects of arginine on marathon runners, and then realized that it was glycine that enhanced the subjects' performance. Similar, albeit inconsistent effects have been reported for GPLC, i.e. Glycine Propionyl-L-Carnitine which improved resistance training performance in Jacobs, et al. 2009, but failed to yield ergogenic effects in a long-term follow-up with negative effects on aerobic acid with high dose (4.5g/day) supplementation of GPLC. Another glycine-compound with mixed evidence of its ergogenic prowess is GAKIC, i.e. glycine-arginine--ketoisocaproate, which has been shown to improve the performance of repeated cycling sprints in Buford, et al. (2004) - a result that could not be confirmed in a follow-up by Beis, et al. (2011), though.

Collagen hydrolysate, a high glycine protein (right bars), turned cata- into anabolism in a recent study in older women on low protein diets whey (left bars) did not (Hays. 2009).
At this point, the existing evidence is thus clearly insufficient to recommend glycine itself or any of the supplement industry's favorite glycine compounds as go-to supplements for athletes. The only thing that comes close is a recent study showing a decrease in nitrogen excretion (a marker of, you guessed it, protein breakdown) and thus reversal of the negative nitrogen balance with high glycine collagen protein - and by the way, the negative nitrogen balance persisted when the older women who participated in this 2-week study consumed a whey supplement (see figure on the left | Hays. 2009).
It is also an amino acid of which the previously cited studies showed that its use as a dietary supplement will (Wang. 2014b)...
  • increased small-intestinal villus height (could reverse leaky gut and will improve nutrient transport), intestinal transport of glycine, plasma concentrations of glycine and GSH, as well as whole-body growth and protein accretion, while 
  • reducing plasma concentrations of ammonia, urea, and glutamine, 
in a dose-dependent manner. Evidence the scientists rightly interpreted as follows: "Based on these lines of compelling evidence, we conclude that glycine is a nutritionally essential amino acid for maximal growth and development of milk-fed young pigs" (Wang. 2014b).
Figure 1: Effects of different doses of glycine on muscle anabolism (blue, left axes) and catabolism (gray, right axes) in C2C12 myotubes - all differences were highly significant (p = 0.001 | Sun. 2016).
With their latest study on C2C12 muscle cells, the scientists were now able to explain both the increased whole-body growth and protein accretion and the reduced ammonia, urea and glutamine concentrations, of which at least the former are clear signs of protein catabolism and thus potential muscle loss - actual gains, however, have yet to be observed outside of model organisms like pigs - also to quantify how much glycine it will take to achieve similar effects as they were observed in vivo.
MAFbx/atrogin-1 and MuRF1 gene activity mediates the degradation of protein and have an inhibitory effect on protein synthesis (Foletta. 2011).
Do I need glycine if I consume whey or BCAAs? With its ability to do both, promote mTOR and inhibit the MuRF1 and atrogin-1 gene expression and thus protein loss in C2C12 myoblasts, Glycine appears to have everything many people ascribe to BCAAs.

The one important difference, however, is that BCAAs don't affect the catabolic muscle genes and catabolism (learn more). While they appear to ameliorate the exercise-induced increase MuRF-1 total protein (Borgenvik. 2012), their effect on the gene expression of the atrophy regulators (see Figure on the right) in muscle cells is nowhere to be found.

Similarly, providing more protein in form of whey protein may further augment your protein synthesis via mTOR increases. What it does not do, however, is to affect the MuRF1 and atrogin-1 mRNA levels. Accordingly, it will only target one side of the net protein accretion equation (gains = existing muscle + muscle synthesis - muscle loss) - or as Stefanetti who studies this effect with different types of resistance exercise in 2014 write: "While WPH supplementation with ECC and CONC training further increased muscle hypertrophy, it did not have an additional effect on mRNA or protein levels of the targets [MAFbx/atrogin-1 and MuRF1] measured" (Stefanetti. 2014).

As discussed in the previous infobox, though, the one, decisive study that would proof practically relevant anti-catabolic effects glycine in healthy human beings, not isolated muscle cells, is not available yet. If you want to target muscle catabolism with supplements, carnitine (Keller. 2013) and HMB appear to be better, but likewise not fully proven candidates | Comment!
  • Borgenvik, Marcus, William Apró, and Eva Blomstrand. "Intake of branched-chain amino acids influences the levels of MAFbx mRNA and MuRF-1 total protein in resting and exercising human muscle." American Journal of Physiology-Endocrinology and Metabolism 302.5 (2012): E510-E521.
  • Buchman, A. L., et al. "The effect of arginine or glycine supplementation on gastrointestinal function, muscle injury, serum amino acid concentrations and performance during a marathon run." International journal of sports medicine 20.05 (1999): 315-321.
  • Buford, BRITNI N., and Alexander J. Koch. "Glycine-arginine--ketoisocaproic acid improves performance of repeated cycling sprints." Med Sci Sports Exerc 36 (2004): 583-587.
  • Hays, Nicholas P., et al. "Effects of whey and fortified collagen hydrolysate protein supplements on nitrogen balance and body composition in older women." Journal of the American dietetic association 109.6 (2009): 1082-1087.
  • Jacobs, Patrick L., et al. "Glycine propionyl-L-carnitine produces enhanced anaerobic work capacity with reduced lactate accumulation in resistance trained males." Journal of the International Society of Sports Nutrition 6.1 (2009): 1.
  • Keller, Janine, et al. "Supplementation of carnitine leads to an activation of the IGF-1/PI3K/Akt signalling pathway and down regulates the E3 ligase MuRF1 in skeletal muscle of rats." Nutrition & metabolism 10.1 (2013): 1.
  • Mascher, Henrik, et al. "Effects of essential amino acid supplementation on markers for anabolic and catabolic response to resistance exercise in female subjects." The FASEB Journal 24.1 Supplement (2010): lb278-lb278.
  • Stefanetti, Renae J., et al. "Influence of divergent exercise contraction mode and whey protein supplementation on atrogin-1, MuRF1, and FOXO1/3A in human skeletal muscle." Journal of Applied Physiology 116.11 (2014): 1491-1502.
  • Sun, KaiJi, et al. "Glycine Regulates Protein Turnover by Activating Akt/mTOR and by Inhibiting MuRF1 and Atrogin-1 Gene Expression in C2C12 Myoblasts." The Journal of Nutrition (2016): jn231266.
  • Wang, Weiwei, et al. "Glycine metabolism in animals and humans: implications for nutrition and health." Amino acids 45.3 (2013): 463-477.
  • Wang, Weiwei, et al. "Glycine stimulates protein synthesis and inhibits oxidative stress in pig small intestinal epithelial cells." The Journal of nutrition 144.10 (2014a): 1540-1548.
  • Wang, Weiwei, et al. "Glycine is a nutritionally essential amino acid for maximal growth of milk-fed young pigs." Amino Acids 46.8 (2014b): 2037-2045.