HMB Supplementation: Pre- or Pre- and Post-Workout? Anti- or Pro-Inflammatory? MA Thesis Offers Food for Thought

Supplement facts: "Is as potent as the weak androgen Oxmethalone aka Anavar!" If that's how you advertise an expensive dietary supplement that tastes like poison, you better make sure your product delivers. For HMB the supplement companies must have overlooked that their clientele is in no way similar to the elderly subjects from their references with their protein deficient diets... the result? An epic fail for both the consumers who felt ripped off and the producers who probably expected this to be a long-term investment!
HMB was once hailed to be as effective as a "weak" androgen such as Anavar. No wonder that dozens of consumers were pretty  disappointed, when they added it on top of their already protein and, at that times more or less coincidentally, leucine-laden diets and saw... nothing. Well, at least no gains that would even remotely remind anyone of Oxymetholone. With no costumer being interest to pay the extra bucks for the (at that time still) very expensive product, it was no wonder that the leucine metabolite β-Hydroxy β-methylbutyric acid (HMB) disappeared from the market relatively quickly.

I bet, the fact that it tastes like poison did not really help either. after all it is downright impossible to add an effective amount of HMB into a powdered supplement, if you do not want to totally ruin the taste of the product.

As a SuppVersity reader you will yet be aware that HMB is still no epic fail (read all older posts on HMB). Its marginal utility, however, is exactly that: Marginal -- at least when someone is taking it on top of tons of leucine rich protein powders, BCAAs and whatever else.

HMB is not useless and there appears to be much we have to learn about it

Despite the fact that it is very unlikely that taking HMB will turn you into a second Phil Health within weeks, its hitherto not fully understood beneficial effects on body fat, its effects on GH and IGF-1 as well as open questions that are related to our own bodies ability to produce HMB from leucine and whether this conversion mediated some of the benefits of the #1 among the BCAAs (=leucine) clearly indicate that there remains a lot to learn about Dr. Steven L. Nissen's 1996 discovery (Nissen. 1996).

One of those things we still have... or I should say had to learn pertains the effect of HMB on the exercise induced expression of inflammatory cytokines, which turned out to be totally different from what Paul Raymond Vulcan, a student who has recently submitted his Master Thesis on the "Role of β-hydroxy-β-methylbutyrate (HMB) on inflammation after eccentric exercise" at the Iowa State University probably expected, when he recruited the 16 female and 16 male, untrained volunteers (mean age 3±0.30y, mean weight 67.5±0.9kg, and mean hight 172.2±0.7cm) for his study.

'Extend your legs' till they burn ;-)

The study consisted of a single exercise + supplementation trial in the course of which the participants underwent the following supplementation regimen:
A note on the supplementation protocol: The way Volcan describes the protocol is at least "suboptimal". If I am getting it correctly (mostly by looking at a graphical outline) the participants in the pre/post trial received HMB not just on day 0, but also on day 1, day 2, day 3 and day 4 - always with lunch and dinner.
"Experimental groups received supplement in one of the following manners: placebo pre- & post-exercise (CON), HMB pre-exercise (PRE) in either a calcium salt form or a free acid gel, HMB pre- & post-exercise (PRE/POST) in either a calcium salt form or a free acid gel.Supplements were given in a double-blind protocol so that investigators were also blind to the contents of the supplements throughout the study.  Originally, the study called for 5 treatment groups with a separation of calcium salt groups from the free acid gel groups. Due to sample sizes, groups receiving the same quantity of HMB were consolidated for statistical reasons." (Volcan. 2012)
While it is certainly somewhat disappointing that we don't have a comparison of the salt and the gel variant of HMB (you will see the first gels hit the market, very soon, believe me),  this is understandable given the small sample size. What is yet a clear greenhorn mistake, however, is that Volcan does not disclose the amount of HMB salt the participants received. He states that the gel syringes contained 3ml but since I have no clue what else (besides HMB) is in the gel, I cannot tell you how much HMB the groups actually received (let alone calculate the equivalent in term of calcium-hmb).

Standard protocol, surprising results

Aside from this lapse the general protocol of the study looks pretty solid. The original challenge on day 0, which consisted of 3 sets of 50 eccentric leg extensions (both legs, 0° to 90°, 60°/sec; 3s per rep, 2 min rest between sets), was preceded and followed by a combination of
  • urine collection, 
  • muscle soreness test, 
  • leg circumference measurements, 
  • blood collection and a 
  • strength test
which took place on day 0 (before the exercise protocol), 24h, 48h, 72h and 96h post. And I guess you could say "fortunately", the analysis of the respective data yielded not exactly what Volcan had expected. Firstly many expected effects did not occur (at least not if you consider only statistical significant inter-group effects), e.g. there were no differences for markers of muscle damage:
  • creatine kinase (CK) 
  • lactate dehydrogenase (LDH) and 
  • 3-methyl histidine (3-MH)
Some did however show a trend (which did not reach statistical significance due to the small sample size) and / or did reach statistical significance at a certain time point only:
  • Figure 1: Peak performance force (in N) on the days after the leg extensions (based on Volcan. 2012). As you can see it's not like there had not been any effects, but with the small sample size few made it over the p < 0.05 hurdle, or put simply were "statistically significant".
    creatine kinase (CK) showed a non-statistically significant reduction in PRE/POST, while it was identical in PRE and CON (1593 IU compared to 3514 IU and 4068 IU; this is a candidate that would almost certainly have reached statistical significance with a larger number of participants, because the CK response shows high inter-individual variability)
  • the decrease in right leg peak force was about 16% in the CON group compared to 9% and 7% in the PRE and PRE/POST groups, respectively
  • the muscle soreness was also not significantly different between groups
  • the difference in the loss of peak force was only significant on day two when the peak performance in the control group dropped significantly (see figure 1)
So far the somewhat disheartening but not actually novel part of the study. With the data in figure 2, however we are actually approaching the real news part of today's post:
Figure 2: Makers of inflammation (IL-1 and TNF-alpha) after 3x50 leg extension on the test day, as well as 24h, 48h, 72h and 96h post (based on Vulcan. 2012)
Take a close look and don't be fooled like I was, when I initially looked at the results and almost automatically assumed that there was a reduction in TNF-alpha and IL-1 in the group that recevived the most HMB (I must say I had only the poor black and white graphs from the original study and not the full-service pack you get, here at the SuppVersity, though ;-)

"I mean, good things reduce inflammation, right?"

Wrong, at least in the case of HMB, which certainly is a good thing, this is not the case. HMB does not reduce inflammation and that despite the fact that it works like a charm for those people of whom we are told that inflammation was the last thing they would need, namely the elderly. And still it appears as if the increased inflammatory response to the muscle damaging exercise on day 0 could actually be part of how HMB works. Volcan realizes that and states:
Just in case you don't want to believe that inflammation could play a beneficial role in the regeneration and even the subsequent super-compensation process at the end of which both your muscle strength and muscle size will go up, I suggest you read the respective installment of the Intermittent Thoughts
"The results of TNF-α and IL-1ra support the theory that inflammation is affected by HMB. In  both cases the CON group experienced a decline in serum concentration and the dip was reduced or limited by supplementation of HMB.  These results could be interpreted as an increase in the inflammatory response following HMB supplementation [...] This suggests that HMB creates a greater inflammatory response which may improve recovery of damaged tissue. When exactly this occurs and how, whether direct or indirect, is not evident from this study. We already kno that proteolysis is affected by HMB and it is also possible that inflammatory cytokines are mediating an optimal recovery." (my emphases in Volcan. 2012)
Edited: While this sounds like an excellent hypothesis there is one thing Volcan has overlooked (and me too, at least initially, thus the update). The current scientific evidence suggest that the IL-1 receptor is like a multifaceted chimera. Or put simply, in its conventional form it will accept IL-1 and thus have exert pro-inflammatory downstream effects. IL-1-RA, which is the variant Volcan measured here, actually does the opposite, though: IL-1-RA blocks the inflammatory effects of IL-1 (Arend. 1997).

In the end, this does not really change my previous assertion that "You need to go beyond the 'all inflammation is bad' paradigm and see 'inflammation', or what we usually refer to as inflammation as what it really is, namely a per se physiological reaction of our bodies that can be good, appropriate and highly desirable or bad, misplaced and highly detrimental depending on the circumstances." It just adds another level of complexity to that statement. And this added dimension can actually explain why HMB works in the elderly, but does not work (at least not to the same degree in young people). Old people have high IL-1 (the pro-inflammatory varieties), young and healthy people don't, so blocking IL-1 signaling will have more pronounced effect in the older ones of you than in the young chaps, who will probably fare quite well with nothing but a leucine rich protein shake.

  • Arend WP. Interleukin 1 receptor antagonist. A new member of the interleukin 1 family. J Clin Invest. 1991 Nov;88(5):1445-51.
  • Nissen SR, Sharp M, Ray JA, Rathmacher D, Rice JC, Fuller Jr, Connelly AS, Abumrad N: Effect of leucine metabolite beta -hydroxy-beta -methylbutyrate on muscle metabolism during resistance-exercise training. J Appl Physiol 1996, 81:2095-2104.
  • Volcan PR. Role of β-Hydroxy-β-methylbutyrate (HMB) on inflammation after eccentric exercise. Graduate Theses and Dissertations. 2012; paper 12501.
Disclaimer:The information provided on this website is for informational purposes only. It is by no means intended as professional medical advice. Do not use any of the agents or freely available dietary supplements mentioned on this website without further consultation with your medical practitioner.