Tuesday, January 21, 2014

Carnitine Shoot-Out: L-Carnitine, Acetylcarnitine, Propionyl- Carnitine - Which One Has the Highest Bioavailability? Plus: 2g LCAR Contain More Carnitine Than 2g ALCAR or PLCAR

What if we don't know what's most bioavailable? Does it really matter?
After years of being labeled as the supplemental non-starter #1, carnitine is got back on the radar of the average and extraordinary gymrat. The reasons are obvious - at least if you read the following SuppVersity articles: "Carnitine Wards Off Fat Gain by Increasing Fatty Acid Oxidation and Total Energy Expenditure" | more, "Carnitine as Repartitioning Agent?" | more, "L-Carnitine Increase Expression of Genes Implicated in Fatty Acid Oxidation, Glucose & Lipid Metabolism" | more. There have been quite a few impressive studies on the benefits of carnitine, lately, and their publication attracted a significant amount of attention in the bodybuilding, health and fitness community.

The question that remains, though, is: Which of the various forms of carnitine works best? Basically that's also what a group of scientists from the University (Hospital) Bern had in mind, when they put gavaged they put their mice on "supplement regimen" containing 2 mmol/kg/day carnitine from plain l-carnitine (LCAR), acetyl-l-carnitine (ALCAR), or propionyl-l-carnitine (PLCAR) for 4 weeks.
Rel. Carnitine content of l-carnitine, acetyl-l-carnitine (ALCAR), propionyl-l-carnitine (PLCAR) and l-carnitine-l-tartrate (LCLT)
Millimol vs. grams - for the carnitines that's a tremendous difference! I know that most of you will be annoyed when they get dosing regimen in millimoles instead of grams, milligrams of micrograms. That's understandable, 'cause it's inconvenient to have to check the molar mass of the given compound, grab the next best calculator and type 2 × 10-3mol * 161.199g/mol to eventually find out that the daily dose we are talking about here is 322.398mg/kg for the mice and thus ca. 26mg/kg or 2g for a human being with a body weight of 80kg (learn how to calculate HEDs).

The inconvenient moles do yet have one major advantage: We don't get into trouble, when we compare "compound molecules" such as the acetyl-carnitine. ALCAR is after all produced by combining L-carnitine and acetyl-CoA and does therefore have a ca. 21% higher molecule mass than the "original" molecule. Practically speaking 500mg ALCAR caps do thus contain 21% less actual carnitine that the basic l-carnitine caps of your neighbor. Aside from increasing the molecular weight, the acetyl-CoA attachment does yet also change it's biological function - in other words: You may get the most carnitine for your money if you buy l-carnitine caps, but whether that equals the most "bang for your buck", is a whole different (non-mathematical) question.
Between week 1 and 2 of supplementation, the mice spent 24 h individually in metabolic cages with supplemented water and food ad libitum. During this period, 24-h urine was collected to assess the excretion of carnitine and acylcarnitines.
After 4 weeks of supplementation, the mice were submitted to an exhaustive exercise on a treadmill, after which they were anesthetized to take the muscle samples that were used to measure the carnitine content you see in Figure 1.
What you cannot see in Figure 1 is that the mice gained an identical amount of weight, and that there were minimal, due to intra-group difference yet statistical non-significant differences in water and thus effective carnitine intake between the LCAR, the ALCAR and the PLCAR groups (it's worth noting that all rodents on carnitine consumed 13-45% more water, so if you feel freaking thirsty, when you're "on" carnitine that may be a natural reaction to the increased). Likewise not shown is are the effect of carnitine on the skeletal muscle architecture, i.e. the ratio of fast-twitch glycolytic and slow-twitch oxidative fibers. The latter remained unchanged - the "specific trophic effect on type 1 fibers which are characterized by an oxidative metabolism" (Spagnoli. 1990) about which Spagnoli et al. speculated in 1990 was absent.
No changes in Skeletal muscle oxidative capacity! In spite of the fact that this is one of the classic promises of carnitine supplementation, the scientists did not observe significant difference in oxygen uptake between animals treated with carnitine or acylcarnitines and control animals and conclude: "These findings indicate that mitochondrial content and capacity (the activity of complexes I, II, and IV of the respiratory chain) remained unchanged in the supplemented compared to the control group" (Morand. 2013)
What you do see in Figure 1, on the other hand, may be misleading, because the existing differences in total carnitine after 4 weeks on the different forms of carnitine were non-significantly increased compared to the control group, so that the bioavailability, the researchers calculated based on the tissue accumulation and urinary excretion of various forms of carnitine were identical, i.e. l-carnitine - 19.8%, acetyl-l-carnitine - 18.6%, propionyl-l-carnitine - 19.1 % (see Figure 3).

It is not unlikely that the absence of significant differences in bioavailability is a direct result of the fact that the acylcarnitines and propionyl-l-carnitine were fully and partially hydrolyzed before reaching the systemic circulation, respectively. Whether there really is a difference to humans, as the scientists claim appears questionable, because the difference between Morand et al.'s rats and Eder's pigs, on the one hand, and the 11 Alzheimer's patients in Parnetti et al. (1992) could well be brought about by age-/health-, and not species-specific differences.

Preformance, not tissue carnitine concentrations count, right?

In the end this may not even be that important given the fact that supplementing with all three forms of carnitine associated with a lower plasma lactate concentration and a better maintenance of the glycogen stores in white skeletal muscle after exhaustive exercise (Figure 2).

As the researchers point out, similarly lowered post-exercise blood lactate concentrations have recently also been reported in humans treated with 4.5 g glycine propionylcarnitine before exercise (Jacobs. 2009).
"These findings indicate that the animals supplemented with carnitine or acylcarnitines tolerated exhaustive exercise metabolically all in all better than the control animals. This may at least partially explain the beneficial effects of carnitine supplementation on physical recovery after intense exercise." (Morant. 2013)
The fact that this occured in the absence of extreme increases in the intramuscular carnitine stores supports a hypothesis that has been put forward by Rebouche et al. in a review about the pharmacokinetics and metabolism of carnitine and acetyl carnitine (Rebouche. 2004), where the researchers asked the question whether an increased carnitine content in target tissues is even necessary for a pharmacological effect of carnitine or whether an increased exchange between the plasma and tissue carnitine pools could be sufficient. Based on the results of the study at hand, the latter appears pissible, if not likely, "the molecular mechanisms responsible for this effect remain speculative, however" (Morant. 2013). Possible explanations Morant et al. propose are:
  • The export of potentially toxic acyl groups from skeletal muscle, as shown in patients on hemodialysis supplemented with carnitine (Vernes. 2006).
  • An effect of carnitine and/or acylcarnitines on capillary endothelial cells, possibly resulting in vasodilation and improved skeletal muscle perfusion and nutrient supply during high-intensity exercise (Jacobs. 2009).
In the end it is thus likely that you can benefit from the provision of 2-5g of carnitine, irrespective of the form you chose (this goes only for LCAR, ALCAR and PLCAR, to make a similar statement about LCLT, which has - among other things - been shown to increase testosterone receptor expression, is a whole different animal).
Bottom line: Despite the pathetic increases in muscle carnitine, the non-existent effects on body weight, carcass and muscle composition and the significant loss of the orally administered carnitine, the study at hand does provide evidence of the ergogenic effects of carnitine. The maintenance of white skeletal muscle glycogen stores, which would actually suggest an increase in fatty acid oxidation, although the corresponing mitochondrial enzymes weren't elevated, the improved lactate concentrations and the minimal, statistically non-signficant, but measurable increases in time to exhaustion are after all ergogenic effects that could provide a metabolic advantage to any trainee.

Figure 3: Comparison of l-carnitine kinetics of  in rodents and humans in response to chronic and acute oral suppl., respectively (Coa. 2009; Morant. 2013)
Whether this metabolic advantage is relevant for the average trainee is yet about as questionable, as the question: "Plain carnitine, ALCAR or PLCAR, what's the best form of carnitine to take?" Based on the results of the study at hand, it would appear that it does not really matter.

If we do yet look back at Table 2 in the Amino Acids for Super Humans" article on carnitine, or the bottom of Figure 3 in this article, it would yet appear as if the results Morant et al. present in their latest paper in the European Journal of Nutrition only support the notion that ALCAR and PLCAR, both of which are sold as a form of "improved" carnitine by the supplement industry, are not the go-to forms of carnitine for the average physical culturist. For him or her, if anything, buying plain l-carnitine over at a bulk supplier of his / her trust would probably be the best option.
  • Eder, Klaus, et al. "Free and total carnitine concentrations in pig plasma after oral ingestion of various L-carnitine compounds." International journal for vitamin and nutrition research 75.1 (2005): 3-9.
  • Parnetti, L., et al. "Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer type." European journal of clinical pharmacology 42.1 (1992): 89-93.
  • Rebouche, Charles J. "Kinetics, Pharmacokinetics, and Regulation of l‐Carnitine and Acetyl‐l‐carnitine Metabolism." Annals of the New York Academy of Sciences 1033.1 (2004): 30-41.
  • Spagnoli, Luigi G., et al. "Morphometric evidence of the trophic effect of L-carnitine on human skeletal muscle." Nephron 55.1 (1990): 16-23. 
  • Vernez, Laurence, et al. "Effect of L-carnitine on the kinetics of carnitine, acylcarnitines and butyrobetaine in long-term haemodialysis." Nephrology Dialysis Transplantation 21.2 (2006): 450-458.
  • Wang, Yong-Xu, et al. "Regulation of muscle fiber type and running endurance by PPARĪ“." PLoS biology 2.10 (2004): e294.