Wednesday, July 22, 2020

Washing Down 6g/d of Beta-Alanine not Enough to Saturate Muscle Carnosine? Beta-Alanine Research Update 07/2020

Carnosine saturation!? It may occur (if at all) only at much higher dosages / longer supplementation periods  than they're currently recommended.
If you've been a faithful SuppVersity reader for the last almost 10 years, you will have noticed that my initial excitement about beta-alanine (#BA) has been fading ever since the classic meta-analysis by Hobson et el. was published in 2012. Yes, there were small benefits (2%) but only in the high(er) intensity 'long sprint' exercises... after having read the latest meta-analysis by Rezende et al. (2020), I am asking myself if this rather mediocre result could be in part due to the relatively low median dose of BA. In the studies Hobson et al. reviewed, the median amount of cumulative #BA intake was 179 g of β-alanine.

Now, Rezende et al. hypothesize that "commonly used BA supplementation protocols may not come close to saturating muscle carnosine content?"

Let's take a look at how a group of Brazilian scientists came up with this idea and why they confidently report the suboptimal dosing schemes as early as in the abstract to their latest paper in Frontiers in Physiology (Note: Mentioning it that early is in itself worth mentioning 😎 because that's the kind of "theory" you'd expect to find as a possible explanation to rather disappointing results in the discussion part of a paper, not necessarily as one of the main outcomes in the abstract).
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Obviously, the saturation effect at 1.5g of beta-alanine per day researchers estimated in the earlier studies did not come as a total surprise, as it mirrored the saturation effect we know from creatine, carnitine and other dietary supplements; however, as the authors of this new meta-analysis point out ...
"[their] data provides new insight into the nature of the MCarn [muscle carnosine levels, which is how BA actually works - by increasing this intra-cellular H+ buffer] response to BA supplementation, and how this differs to other commonly used dietary supplements, such as creatine" (Rezende 2020).
In contrast to creatine, #carnosine, which is the actual active downstream metabolite you want to boost with BA supplements, does not saturate within 5 days of high-dose (loading) supplementation and depend on baseline levels with largest benefits in athletes w/ low(er)-creatine.

Does it take almost 400g (cumulative) to get to ~50% max muscular BA levels?

Using data from their meta-analysis, Rezende et al. predicted a maximum effect of BA supplementation (Emax) at 3.0 [50% | CrI: 2.2 – 3.7]. This corresponds to an estimated total cumulative dose of 377g [50% | CrI: 210 – 494].
What can you do to get the most of whatever dose of beta-alanine you may be taking? In view of the fact that scientists have hitherto believed that with 2x1.5g/d pretty much everyone will arrive at maxed-out #carnosine levels. It is thus rather logical and not negligent that co-variates that determine how BA is absorbed, metabolized, and stored have not gotten much scientific attention. In fact, I could find only one recent paper dealing with the topic in some detail and Perim et al. 2019 had to resort to secondary, tertiary, or merely coincidental observations in a plethora of studies to identify the following factors:
  1. total and relative dose -- previous research confirms that 'more helps more' but as you can see in Figure 2 the response is non-linear. So don't expect 2x the effect from 2x3g/d vs. 2x1.5g/d.;
  2. supplement duration - scientists still believe that BA doesn't have to be consumed daily, because it takes weeks for elevated levels to return to baseline, but to keep at super-natural carnosine levels you'd better do just that;
  3. Figure 1: Overview of the few known modulators of BA supplementation's effects on muscle carnosine; there's still room for research here - especially when saturation is not achieved as easily as previously thought.
  4. form of beta-alanine -- you will have seen that supplement vendors sometimes include time-released beta-alanine in their preparation, the only rationale to do so is to circumvent the tingling (of which we still don't really know what causes it) some people don't like (on average, I know many people who love just that 'I feel it works' effect of BA and I am sure that's why time-released is NOT really popular), if the absence of spikes in the blood level of beta-alanine affect its ability to boost muscular carnosine levels is hitherto under-investigated, with Decombaz et al. suggesting(!) that you may pee out a little less at low(ish) dosages, related research on the downstream effects on carnosine is conflicting with a study providing 4.8g/d showing no (Stegen 2013), and a study providing 6g/day for 28 days (Varanoske 2019) detecting significant benefits of slow-release;
  5. effects of food (CHO and insulin) -- while the reliance of the taurine transporter on the insulin-sensitive Na+/K+-ATPase pumps would suggest so, scientists have struggled to demonstrate actual benefits of co-ingestion of CHOs or foods in general, only a single study (Stegen 2013) found muscle-specific benefits for the soleus (slow twitch) but no effect on the gastrocnemius (fast-twitch) muscle, others (non-muscle specific) demonstrated no insulin-advantage (Gonzales 2020).
Before we call it a day with the interactions I should probably point out that research has shown quite consistently that (esp. sprint and/or resistance) training is an incentive for your body to increase muscle carnosine. As a study in vegetarians (de Salles Painelli 2018) shows this increase occurs irrespective of dietary or supplementary BA intake, though - the effects of beta-alanine supplements, on the other hand, does not seem to be augmented by exercise.
Figure 2: The data on which we can rely when making prognosis about is everything but extensive... both in the time and dosing domain (Spelnikov 2019).
And, as the plot depicting the carnosine content in muscle biopsies according to the duration of supplementation in Figure 2 suggests, there's room for more!
"An extrapolation of posterior samples from the Emax model was performed to estimate probabilities that percentage of maximum effect could be achieved with cumulative doses ranging from 1000 to 1500g. These results estimated, for example, that the probability of obtaining at least 70% of maximum effect with a cumulative dose of 1000g was 0.68" (Rezende 2020).
In the absence of actual studies that were designed to figure out what the optimal value is one needs to interpret the results of the extrapolation at high(er) than experimentally investigated amounts, we do yet have to be skeptical about the accuracy of their prediction.

Don't be fooled by the meta-analysis, as any meta is only as reliable as its input data

After all, the estimates at the higher end of the curve described in Figure 2 suffer from a paucity of data from studies using high(er), let alone very high doses. In addition, we should not forget that these questionable estimates are based on the median expected effect, and considerable inter-individual variation is likely.
Figure 3: Mean ΔM-Carn in m. gastrocnemius (Gastr) and m. tibialis anterior (TA) following 14 BA supplementation at different dosages. Data from Stellingwerff et al. as published in (Spelnikov 2019).
The model also indicates that MCarn increase in response to BA supplementation is non-linear, and that the greatest increases occur in the earlier stages of supplementation. In that, it is important to consider, as Spelnikov & Harris do in their model, both, synthesis and decay of muscle carnosine. In their model, tissue saturation represents the point at which the rates of synthesis match decay, and so content remains constant despite continued supplementation.

The exact point, and nature, of this 'saturation point' is not currently known. 

Moreover, the possibility of tissue/muscle-specific saturation points complicates things even further; and, eventually, it's not even clear that further increases in carnosine level are actually associated with measurable performance and/or health benefits - despite the fact that  "[t]heoretically, the greater the increase in MCarn content, the greater its ability to buffer, and to contribute to other processes such as anti-oxidation and anti-glycation" (Rezende 2020). Logical, but not fully supported by science, as Rezende et al. point out:
"But evidence on [the more carnosine = more performance] hypothesis is conflicting. Two individual studies reported that larger MCarn increases were associated with greater performance effects, but this assertion is not supported by meta-analytic data, which indicates that the total dose ingested does not influence its effect on exercise performance" (Rezende 2020). 
That we don't know if we're chasing elusive and useless increases in carnosine levels is yet by no means the only important research gap Rezende et al. found ...
    Reductions in muscle and especially serum taurine have indeed also been observed in humans, but the fact that they do not occur in lower dose studies and cannot be observed consistently in studies using higher dosages (6g) suggests that they shouldn't be a problem for the average BA user | more
  • we don't know threshold values or ranges at/in which performance benefits occur;
  • the effect of supplementation strategies such as meal co-ingestion, intake in proximity to training or intake in slow-release capsules is not fully understood (check out the previous infobox containing Figure 1 for some pointers;
  • safety and advocacy are still a problem; not the least because we still don't understand (a) what the 'BA tingles' are, and (b) whether the "paresthesia" (i.e. the "tingling") is in fact as harmless for the CNS as researchers have come to believe; moreover, (c) taurine depletion can become an issue at higher dosages (animal studies using much more BA than those max 3x1.5g/d commonly used in human studies suggest just that);
  • that the co-administration of histidine is beneficial, maybe even necessary has only been refuted for limited time low(er) dose supplementation.
Accordingly, future studies should quantify the carnosine loss at rest and during exercise (individual data from the meta-analysis at hand suggests approximately 4 mmol/kgal cross a 4-week period).

We also need future studies that assess the influence of age and provide the hitherto insufficient data in older groups, and generate data for younger (teen or earlier) groups... and while we are at it: It would obviously be nice to get to understand why women have generally lower carnosine concentrations than men and what that means for the benefits they can expect to see.

Until we have data to support the extrapolations from Rezende's meta-analysis, it is unwarranted to recommend taking more than 6g/d of beta-alanine ... ideally in 3-4 smaller servings. Still, the fact that saturation is not as easily achieved as is the case for e.g. creatine is something worth remembering.
This is Adam Virgil's illustration of another recent meta-analysis focusing more on the question(s): "What can you expect of beta-alanine | check it out in BMJ
What else is going in the buffered world of beta-alanine? Now that we are about to delve into a SuppVersity-ish look on what else has been going on in beta-alanine research.

Let me remind you, though, one thing you shouldn't forget is that beta-alanine clearly isn't (and will not be at higher dosages) the TOP ergogenic supplement producers want you to believe. It's probably better than BCAAs but, as the name implies, a 'supplement' - not a must-have! 🤔

For beta-alanine as a supplement there's almost no other research to freak out about in 2020, yet: Smith et al. found no effect of BA on anaerobic exercise performance in collegiate rugby athletes. And the only effect Varanoske et al. observed in their high-dose (12g/day), short-duration BA supplementation before intense military training was the onset of negative mood states in healthy, recreationally-active males - the beneficial effects on cognitive function or circulating BDNF the authors expected did not occur, though... worth mentioning: with a daily dose of 12g/d the last-mentioned study should remind you of being skeptical about "more helps more" - although, yes... could be the short duration 🙄 | Comment!
References:
  • de Salles Painelli, Vitor, et al. "HIIT augments muscle carnosine in the absence of dietary beta-alanine intake." Medicine & Science in Sports & Exercise (2018).
  • Décombaz, Jacques, et al. "Effect of slow-release β-alanine tablets on absorption kinetics and paresthesia." Amino acids 43.1 (2012): 67-76.
  • Gonçalves, Lívia de Souza, et al. "Insulin does not stimulate β-alanine transport into human skeletal muscle." American Journal of Physiology-Cell Physiology 318.4 (2020): C777-C786.
  • Hobson, Ruth M., et al. "Effects of β-alanine supplementation on exercise performance: a meta-analysis." Amino acids 43.1 (2012): 25-37.
  • Perim, Pedro, et al. "Can the skeletal muscle carnosine response to beta-alanine supplementation be optimised?." Frontiers in Nutrition 6 (2019): 135.
  • Rezende, Nathália S., et al. "The muscle carnosine response to beta-alanine supplementation: a systematic review with bayesian individual and aggregate data e-max model and meta-analysis." Frontiers in physiology (2020).
  • Saunders, Bryan, et al. "Infographic. A systematic review and meta-analysis of the effect of β-alanine supplementation on exercise capacity and performance." British Journal of Sports Medicine (2019): bjsports-2019.
  • Spelnikov, Dmitry, and Roger Charles Harris. "A kinetic model of carnosine synthesis in human skeletal muscle." Amino Acids 51.1 (2019): 115-121.
  • Stegen, Sanne, et al. "Meal and beta-alanine coingestion enhances muscle carnosine loading." Med Sci Sports Exerc 45.8 (2013): 1478-85.
  • Varanoske, Alyssa N., et al. "Comparison of sustained-release and rapid-release β-alanine formulations on changes in skeletal muscle carnosine and histidine content and isometric performance following a muscle-damaging protocol." Amino Acids 51.1 (2019): 49-60.