Arachidonic Acid – More Muscle Mass and Strength?

Arachidonic Acid – More Muscle Mass and Strength?

In this article, we are going to analyze the intake of arachidonic acid to gain strength and muscle mass. Let’s going to see what would be its optimal dose, how to take it…

What is Arachidonic Acid?

It is a polyunsaturated acid with a eicosatrienoic structure (made up by a long chain of 20 carbons) and 4 double bonds (that is why it is unsaturated).

It is an omega 6 fatty acid because its first double bond is located in the sixth bond if we count from the last carbon atom.

Chemical structure of arachidonic acid

Figure I. Chemical structure of arachidonic acid and signalling of its double bonds

This fatty acid is specially distributed in the immune system cells and the cell membranes from the remaining tissues. Consequently, this makes them more flexible, improving their fluidity.

In addition, this acid is in charge of regulating the immune system, allergies and inflammation, apart from improving the mood and appetite

Sources of Arachidonic Acid

For example, egg, salmon, tuna and lean and fatty meat are excellent sources of arachidonic acid.

Although we can also obtain it from linoleic acid supplementation. In fact, this element is transformed into arachidonic acid by a series of enzymes (desaturases and elongases).

Metabolism of linoleic acid

Figure II. Metabolism of the synthesis of arachidonic acid from linoleic acid by desaturases and elongases. (Hanna and Hafez, 2018)

Why take Arachidonic Acid?

However, arachidonic acid has been used for decades by “gym bros” due to an apparently logical physiological principle

After the workout, there are micro-fractures in the extracellular matrix that release pro-inflammatory molecules (autocrine, paracrine and endocrine). Consequently, this activates the immune system, triggering a series of anabolic reactions to strengthen the cell structure before a new stimulus.

Therefore, using a pro-inflammatory fatty acid that increases the availability of the precursors for the synthesis of these pro-inflammatory molecules… would be ideal to enhance the anabolism, right?

Well, let’s see if that is correct:

How does Arachidonic Acid work?

The body metabolizes arachidonic acid through several pathways depending on the context: these could be enzymatic or non-enzymatic pathways.

Above all, we are interested in the metabolization pathway mediated by Cyclooxygenase. Although have already talked about it in the post about anti-inflammatories and hypertrophy)

Cyclooxygenases are isoenzymes which are in charge of producing prostaglandins (PGH2, PGE2, PGD2, PGF2-alpha), prostacyclin (PGI2) and thromboxanes (TXA2, TXB2). In other words, prostanoids.

When in a basal state, the cells produce very low amounts of these molecules. However, when there is inflammation (like during the workout), this production increases exponentially, enhancing the inflammation signals. Consequently, our body recruits leukocytes, immune cells, cytokines and myokines that will help to repair the tissue and get rid of the waste substances.

Despite not completely knowing the mechanisms of each prostanoid for hypertrophy, we know that COX inhibitors block the prostanoid synthesis. Consequently, they hinder the growth of muscle mass in the short-long term by buffering the inflammatory response caused by the workout.

Palmer’s Discovery

Nevertheless, not all prostanoids are good. In 1990, Palmer showed how prostaglandins PGE2 and PGF2-α are in charge of regulating the protein turnover. On the one hand, PGE2 regulates the proteolysis, while PGF2-α regulates the protein synthesis, as well as the proliferation, differentiation and fusion of satellite cells.

Synthesis of PGE2 and PGF2

Figure III. Model of the mechanisms that affect the synthesis of PGE2 and PGF2-α and their effect on the protein turnover (Palmer, 1990)

Moreover, according to Markworth and Cameron-Smith (2013), PGI2 and PGF2-α increase the size of muscle fibers by enhancing the fusion of satellite cells. In fact, they stimulate the myogenesis, unlike the PGD2 which produce the opposite effect.

Therefore, if we observe the physiological theory, taking Arachidonic Acid is a double edged sword: it can have potentially positive and negative effects on the protein metabolism and muscle-skeletal hypertrophy. But, is there any study about all this?

Studies about Arachidonic Acid Supplementation

The truth is that in vivo studies show a mixed evidence about the effectiveness of arachidonic acid supplementation

Most of them do not show significant evidence in terms of muscle growth or strength when compared to the control group (Roberts et al., 2016; De Souza et al., 2016). Although it seems that the power increases considerably thanks to the intake of arachidonic acid. In fact, this has been proven in the studies that we previously mentioned through the Wingate test.

Effects of taking arachidonic acid

Figure IV. Effects of taking 1.5g of arachidonic acid for 50 days on peak power measured with a Wintgate Test vs placebo. (Roberts et al. 2016)

Problems with the studies

Above all, the main problem is that most of the studies do not have a proper methodological structure. This is due to multiple factors that can alter the final results, in other words, they have a high risk of bias.

In fact, the study by Roberts et al., 2016 used corn oil capsules as placebo. Although corn is a source of linoleic fatty acids, precursors of arachidonic acid.

Therefore, the study was conducted without standardizing certain variables that can alter the results. All in all, this only makes us questions their reliability.

Effect of arachidonic acid in athletes

Mitchell et al. (2018) tried to find out the metabolic responses caused by arachidonic acid in trained subjects

As we previously mentioned, the evidence of its effectiveness is mixed. But a simple way of checking its potential is looking at the effects of the product on different signalling pathways.

Evidently, the hypothetical mechanism of arachidonic acid that improves the muscle-skeletal hypertrophy is:

Increasing the fibril response of the muscle protein synthesis

But, do you know what they found out in this study?

Myofibril response synthesis

Figure V. Early and late response of the post-workout myofibril protein synthesis (A) and response (0-4h) (B); between the group that took arachidonic acid (black bar) and control group (white bar). (Mitchell et al. 2018)

Taking 1.5g of arachidonic acid did not alter the myofibril response of the post-workout protein synthesis in the short (0-2h) or long term (2-4h). Therefore, taking arachidonic acid around the workout did not increase the muscle protein considerably

Arachidonic acid does not affect the expression P70S6K, a kinase that phosphorylates after activating the protein macro-complex mTORC1.

P70S6K changes

Figure VI. Changes in the post-workout expression of P70S6K, after 2 and 4 hours; between the group that took arachidonic acid (black bar) and control group (white bar). The asterisks show statistically significant differences with the pre-workout (Mitchell et al., 2018)

In addition, the authors proved that the post-workout ERK-1/-2 response did not change between the control and experimental group.

Therefore, arachidonic acid did not affect the PI3K-mTORC1 or RAS-MEK-ERK pathways. This is quite complex, that is why I suggest reading an article about the different responses to hypertrophy. There, we explain all these terms and concepts in more detail

Does arachidonic acid work?

Then, it is worthless right? Well, it is not that simple…

There are many studies conducted on humans that show how acute post-workout muscle protein synthesis can not result in muscle mass gains. Although there are theories that point that more post-workout muscle synthesis repeated throughout time would.

But the study also assessed the response of NCAM+ cell expression. These cells are found in muscle myofibrils and they are in charge of fixating satellite cells to the myofibril.

Have you ever heard about muscle memory? If not, check the article we wrote about it: it differentiates the fusion of satellite cells and myofibrils and increases the number of myonuclei in the myocytes (polynuclei) present in muscle fiber

Let’s not forget that the nucleus is the one in charge of setting the protein synthesis into motion.

Therefore, increasing the amount of a marker that signals the presence of satellite cells in the muscle fiber is very useful for long-term hypertrophy.

NCAM + cells per 100 myofibers

Figure VII. Changes in the amount of NCAM+ cells/100 myofibrils pre- and 48h. post-workout (B) and change % regarding the pre- (C) between the group that took arachidonic acid (black bar) and control group (white bar). The asterisks show statistically significant differences with the pre-workout (Mitchell et al., 2018)

Likewise, it considerably increases the late post-workout expression of the UBF protein. This is one of the components of the complex that controls the ribosome biogenesis.

Let’s not forget that ribosomes are the structures to which amino acids bind to form peptide protein chains. In other words, they are involved in the protein synthesis.

Protein Synthesis

Protein synthesis infographic

Figure VIII. Infographic of the protein synthesis (Instagram: @sportsciencemaniac)

Therefore, if we have more “workers” and more “factories”, what will happen? Evidently… We will produce more goods (protein). Then, it seems that it works, right? Yes, it does, but not in the way we used to believe

Dose of arachidonic acid

A study conducted by Markworth et al. (2013) assessed the effects of using arachidonic acid supplementation on myotube C2C12 cells in mice (In vitro)

In the end, the results were quite interesting; the myotubes structure grew depending on the dose of arachidonic acid supplementation. Moreover, the myotubes were thicker when they used a higher dose of arachidonic acid.

Myosin

Figure IX. Graphic representation of sarcomere myosin through immunofluorescence that shows changes in the size and protein accretion of the myotubes. Differentiation of the myoblasts with different doses of arachidonic acid. Markworth et al. (2013)

Do you see the squares in the previous image?

  • The green lines are the myotubes (immature structures from the muscle tissues)

Do you see how the higher the number associated with each square (dose) the thicker they are?

  • This means that the presence of arachidonic acid during the myogenic differentiation (that starts with the workout) increases the size of the myotubes depending on the dose

Despite that fact that arachidonic acid increases their size, when they administered higher doses (50mcM and 100mcM) they did not only grow. In fact, they seemed to suffer a progressive degeneration (induced cytotoxicity).

Arachidonic acid dose

Figure X. Myotube size change with different doses of arachidonic acid. (B) and the amount of protein from the myotubes during 3 days of induced differentiation in the myoblasts (C). Markworth et al. (2013)

What conclusion can we draw from all this? That taking high doses of arachidonic acid is far from being an useful strategy to stimulate the hypertrophy. Particularly because it could actually reduce the size of the muscle tissue.

These same authors found clear visual differences in the myotubes from the myoblasts between the group that took arachidonic acid and the control group. In fact, you can see it clearly in the previous image.

Can you see how the green lines (myotubes) are thicker?

Veh AA

Figure XI. Graphic representation of sarcomere myosin through immunofluorescence that shows changes in the differentation of myoblasts in presence (AA) or absence (Veh) of arachidonic acid for 3 days. Markworth et al. (2013)

The authors concluded that these changes were not due to a proliferation of myoblasts (immature cells). Rather, the differentiation of the cells without arachidonic acid increased the number of myotubes (even more than with arachidonic acid). But these were “immature”, having ≤2 nuclei/myotubes

Despite having a very positive ratio of myonuclei/myotubes in the group that took arachidonic acid, there were less myotubes. In fact, between the 72h images there are more green lines in the control group than in the treatment group. But these myotubes had ≥5 myonuclei per unit, that is, there were less myotubes but with more myonuclei in each one of them.

Do you remember that more myonuclei meant more hypertrophy in the long term, right?

Myotube differentation

Figure XII. Changes in the total amount of myotubes, changes in the % of myotubes that have 5 myonuclei or more per unit and ratio of myonuclei/myotube. Changes in the group that took arachidonic acid (black bar) and control group (white bar) throughout three days. Markworth et al. (2013)

To sum up, the authors found out that using a cyclooxygenase-2 enzyme inhibitor (the one that transforms arachidonic acid into prostanoids) reduces the hypertrophy.

NS-398 and Indomethacin

Figure XIII. Graphic representation of sarcomere myosin through immunofluorescence in the C2C12 cell myoblasts that shows the inhibition of the myogenesis. This is due to the intake of a non-selective non-steroidal anti-inflammatory (Indomethacin) and a COX-2 selective one (NS-398) in different doses. Markworth et al. (2013)

However, when the authors artificially increased the amount of prostaglandins (not with arachidonic acid), the myotubes did not suffer the same positive adaptation than with arachidonic acid.

Conditioned and Direct Arachidonic Acid

Figure XIV. Graphic representation of sarcomere myosin through immunofluorescence in the C2C12 cell myoblasts that shows changes in the differentiation of the myoblasts after using arachidonic acid. Either directly or through a medium that contains prostaglandins in order to mask the effect of arachidonic acid (conditioned) (A). % of myotubes with 5 myonuclei or more before (white bar) and after the treatment (black bar) (B) and diameter of the myotubes (B). Markworth et al. (2013)

How to take arachidonic acid

In general, all those who want to stimulate the muscle hypertrophy with arachidonic acid should take 1.5g before or after the workout.

Moreover, we do not know if this effect is acute or if it works by “saturation”, discontinuously every 4-8 weeks. Actually, these are the protocols used for most studies. In other words, you have to cycle its intake, every 8 weeks and stop using it the same time that you were taking it.

Warnings

Finally, it is important to understand that we are talking about a pro-inflammatory fatty acid

A mild inflammation is one of the side effects of many diseases and degenerative disorders (cancer, arthritis, aging). Therefore, inducing a chronic inflammatory state to increase the hypertrophy can negatively affect our health.

Once again, this is pure speculation from our knowledge about metabolic physiopathology and all the studies that have been published throughout time. In fact, there is no study that associates the intake of arachidonic acid (per se) with a worse health.

Once again, we would like to emphasize that this article has been written to provide academic information. It is aimed at health professionals and it should not be regarded as medical advice or similar.

Alfredo Cristóbal Valdés García is not responsible for any action based on the reading of this article, that is not its purpose; the reader is responsible for the use of this academic information.

Consult a physician before doing anything or taking any supplement mentioned in this article

Conclusions

All this is quite interesting, but unfortunately taking arachidonic acid to gain strength and muscle mass involves the effects of prostanoids.

As we have previously mentioned, they can have an acute or chronic effect on hypertrophy. In fact, it is still a mystery despite having general positive reviews, the evidence is mixed

Bibliography

  1. De Souza, E. O., Lowery, R. P., Wilson, J. M., Sharp, M. H., Mobley, C. B., Fox, C. D., … Roberts, M. D. (2016). Effects of Arachidonic Acid Supplementation on Acute Anabolic Signaling and Chronic Functional Performance and Body Composition Adaptations. PloS One, 11(5), e0155153.
  2. Hanna, V. S., & Hafez, E. A. A. (2018). Synopsis of arachidonic acid metabolism: A review. Journal of Advanced Research, 11, 23–32.
  3. Markworth, J. F., & Cameron-Smith, D. (2013). Arachidonic acid supplementation enhances in vitro skeletal muscle cell growth via a COX-2-dependent pathway. American Journal of Physiology. Cell Physiology, 304(1), C56-67.
  4. Mitchell, C. J., D’Souza, R. F., Figueiredo, V. C., Chan, A., Aasen, K., Durainayagam, B., … Markworth, J. F. (2018). Effect of dietary arachidonic acid supplementation on acute muscle adaptive responses to resistance exercise in trained men: a randomized controlled trial. Journal of Applied Physiology (Bethesda, Md. : 1985), 124(4), 1080–1091.
  5. Palmer, R. M. (1990). Prostaglandins and the control of muscle protein synthesis and degradation. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 39(2), 95–104.
  6. Roberts, M. D., Iosia, M., Kerksick, C. M., Taylor, L. W., Campbell, B., Wilborn, C. D., … Kreider, R. B. (2007). Effects of arachidonic acid supplementation on training adaptations in resistance-trained males. Journal of the International Society of Sports Nutrition, 4, 21.
  7. Tallima, H., & El Ridi, R. (2018). Arachidonic acid: Physiological roles and potential health benefits – A review. Journal of Advanced Research, 11, 33–41.

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About Alfredo Valdés
Alfredo Valdés
A specialist in Pathophysiology and biomolecular effects on nutrition and sportive activity who will show you the elaborate world of sports nutrition in his articles, employing a simple and critical writing.
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