Monday, June 11, 2012

Lean & Muscular W/ Alpha Lipoic Acid? You Could Be Just as Lean, But More Muscular W/out "Nutrient Repartitioner"!

Image 1: Lean enough? Ever thought it may be better to stop taking your ALA, now?
I know what you are probably thinking right now: "Not yet another rodent study on the insulin sensitizing effects of alpha lipoic acid!" And in fact, you would be totally right if the results of this very study, which is going to be published in the next issue of the European Journal of Nutrition could not just save you a lot of money but also propel, or rather restore your lean mass gains. After all, the real-world implications of the differential effects of alpha lipoic acid supplementation Prieto-Hontoria et al. observed in lean vs. obese rodents would suggest that your expensive "nutrient repartitioner" may repartitions the energy away from your muscles and thus impair your gains. Put simply: Alpha lipoic acid keeps you lean, yeah... lean, but probably undermuscled!

Now you are listening, right? 

Well, let's see what the Spanish researchers did, then. Basically Prieto-Hontoria and his colleagues repeated an experiment many other researchers have conducted before. They took a bunch of young male Wistar rats and fed them a...
  • regular diet with a macronutrient ratio of 20/67/13 (protein, carbs, fats)
  • regular diet + 0.25g racemic alpha lipoic acid per 100g chow
  • high fat diet with a macronutrient ration of 20/20/60 (protein, carbs, fats)
  • high fat diet + 0.25g racemic alpha lipoic acid per 100g chow
And while the existence of a ALA control group on a normal diet alone would be a very welcome twist on your average "lipoic acid helps vs. diet induced insulin resistance / obesity"-study, the existence of two pair-fed groups
  • regular diet, pair-fed receiving the same amount of chow as the regular diet + ALA group consumed voluntarily, but without the ALA content
  • high fat diet, pair-fed receiving the same amount of chow as the high fat + ALA group consumed voluntarily, but without the ALA content
Allows for unique conclusions in terms of which effects are actually ALA-mediated and which ones are nothing but a side-effect of the anorexic (=appetite / food intake reducing) effects of alpha lipoic acid.

What's good for obese pre-diabetics on the standard American diet ...

Body weight and food intake were recorded every 2–3 days. And blood glucose, insulin, HOMA-IR, white adipose tissue mass, body total body weight gain, serum adiponectin levels and AMPK levels in white and brown adipose tissue, as well as skeletal muscle were determine at the end of the 8-week experimental period.
Figure 1: Effects of 8 weeks of supplemental alpha lipoic acid on body composition of rodents on different diets; active treatment vs. control (left) and active treatment, pair-fed (with active treatment) and control (right; data based on Prieto-Hontoria. 2012)
If you take a look at the left graph in figure 1 you see, what you probably would have expected. The rodents in the ALA groups (ad-libitum fed) gained significantly less body weight and had significantly less body fat than their peers, regardless of which diet they were on. Ok, the "lean mass" (here simply the difference between total and fat mass and thus not necessarily 100% identical to muscle mass - the rodents in the ALA groups could for example also have lower bone or organ weights) is lower, but alas, at least they are lean! And you are right, lean they are, but their pair-fed peers in the regular diet group, who received the exact same amount of food, but without any supplemental alpha lipoic acid, were exactly as lean, but made significantly greater gains (cf. figure 1, right)!

... can be detrimental for healthy, lean individuals whose ideal body image is not just skinny!

Figure 2: AMPK expression in white & brown fat and muscle (top, based on Prieto-Honta. 2012), and implications (bottom)
Now that we know about beneficial effects for SAD dieters and the detrimental effects for physical culturists, it's about time to take a look why on earth this happens and the answer - as counter-intuitive as that may sound, is via downregulation of AMPK (click here to read my dissertation on the "mTOR <> AMPK Seesaw ") - yes, you heard me right. As it turns out the "beneficial" effects of ALA on 5' adenosine monophosphate-activated protein kinase activity are tissue- and downstream effects diet-specific. Therefore, the detrimental effects of the decreased skeletal muscle and brown adipose tissue AMPK activity are outweighed by the increase in white adipose tissue AMPK activity, the researchers observed in ALA supplemented rodents from both groups, was outweighed by the increase in white adipose tissue AMPK activity (and increases in adiponectin, see figure 2) only in the high fat diet group. The rodents who received the normal chow, on the other hand, achieved a much more favorable body composition by simply mimicking (obviously through pair-feeding and not voluntarily) the ALA induced (small) reduction in food intake.

"Hold on, what's all that AMPK b*s* about? Where's the connection to being lean & muscular?"

The downregulation of BAT AMPK activity, on the other hand, is as the analysis of the role of AMPK in cold thermogenesis by Mulligan et al. suggests, is a clear downside of ALA (Mulligan. 2007) and could in fact be related to its previously reported negative effects on thyroid metabolism, respectively the conversion of the "inactive prohormone" T4 to the metabolically active T3 (Segermann. 1991). Likewise, the reduction of skeletal muscle AMPK is not a benefit as the data in figure 1 clearly shows that the bro-scientific claims about muscle loss due to increased skeletal muscle AMPK activity don't hold. Something that should actually be obvious, in view of the role AMPK plays skeletal muscle glucose uptake, glycogen and ATP regulation (Kurth-Kraczek. 1999; Musi. 2002), and mitochondrial biogenesis (Hardie. 2010).
Figure 3: Insulin, HOMA-IR, adiponectin and adiponectin relative to white adipose tissue weight in control, pair-fed (same food intake as ALA, but no supplement) and ALA supplemented rodents after 8 weeks (based on Prieto-Hontoria. 2012)
Still, due to the profound increases (total and relative to fat weight) in adiponectin (cf. figure 3), a fat-derived hormonal with well-established insulin-sensitizing and anti-obesity effects (Yamauchi. 2001; Shehzad. 2012), which showed a statistically significant correlation (after correction for adiposity) with the HOMA index, a recognized marker of insulin resistance, and its preventive effects against diet induced obesity, alpha lipoic acid should remain among the recommended supplements for obese, insulin resistant or diabetic subjects.

Is alpha lipoic acid for you? If you are lean, this study says "NO"!

Image 2: If you are the fat endo at the bottom, ALA could be for you. If you are the guy on the left, mild cutting and bulking w/out ALA is for your. And if you are on the right, you better spend your money on protein, creatine, BC/EAAs.
Its merit for lean physically active people, who consume a energetically appropriate whole-foods diet and strive to build a lean and muscular, not just a skinny physique, its usefulness is yet somewhat questionable. After all, the pair-fed animals had an equally low amount of body fat as their peers on ALA, but statistically significant more lean body mass; and I personally don't believe that it is a realistic assumption that these effects could be countered by simply eating more without having negative effects on the total amount of body fat you would accumulate on this heavy-duty bulk.

Your best bet would to try and "exercise away" the negative effects on  skeletal muscle AMPK expression, but let's be honest: Would you rather wear a helmet instead of simply stopping to hammer your head against the wall? You would, ha? In that case you are beyond help, I guess... go ahead then and do what works for your obese neighbor.

Note (I know someone is going to ask this): If anyone can show me peer-reviewed in-vivo data that confirms the constantly made claim that the physiological effects (not the petri-dish or XYZ-essay effects) of R-ALA are superior, not just on a gram-per-gram base, but qualitatively, tho those of the cheap and obviously less profitable racemic ALA (= natural mix of R- and S-ALA), I would be inclined to answer the question "wouldn't taking R-ALA maybe make a difference".

  • Hardie DG. Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism. Proc Nutr Soc. 2011 Feb;70(1):92-9. Epub 2010 Nov 11.
  • Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW. 5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes. 1999 Aug;48(8):1667-71.
  • Mulligan JD, Gonzalez AA, Stewart AM, Carey HV, Saupe KW. Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse. J Physiol. 2007 Apr 15;580(Pt. 2):677-84.
  • Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002 Jul;51(7):2074-81. 
  • Prieto-Hontoria PL, Pérez-Matute P, Fernández-Galilea M, Martínez JA, Moreno-Aliaga MJ. Effects of lipoic acid on AMPK and adiponectin in adipose tissue of low- and high-fat-fed rats. Eur J Nutr. 2012 Jun 5. [Epub ahead of print]
  • Segermann J, Hotze A, Ulrich H, Rao GS. Effect of alpha-lipoic acid on the peripheral conversion of thyroxine to triiodothyronine and on serum lipid-, protein- and glucose levels. Arzneimittelforschung. 1991 Dec;41(12):1294-8.
  • Shehzad A, Iqbal W, Shehzad O, Lee YS. Adiponectin: regulation of its production and its role in human diseases. Hormones (Athens). 2012 Jan-Mar;11(1):8-20. 
  • Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001 Aug;7(8):941-6.