How Leucine, HMB & Creatine Can Inhibit Myostatin (Explained)


Evidence-Based. Scientifically Reviewed by Michael Sharpe, MSc.

Leucine, HMB and creatine all work to reduce the actions of myostatin by increasing Akirin-1/Mighty mRNA expression. They may be synergistic in their effects due to their ability to enhance muscle growth in different ways.

Muscle cells produce a protein called myostatin, which inhibits their own growth. Because deactivating myostatin allows you to gain muscle growth and strength, scientists are researching various myostatin blockers for the treatment of muscular atrophy and other disorders.

However, it seems that a few over-the-counter supplements may reduce the actions of myostatin.

Researchers discovered that by giving athletes a creatine supplement, they were able to suppress myostatin production.

scoop of creatine hmb and leucine supplementThe Study

The researchers treated young C2C12 muscle cells to myostatin as well as three well-studied bodybuilding supplement ingredients: creatine, leucine, and HMB.

Below are meanings for the abbreviations used in the study.

  • DM/CTL: Control group
  • CrM: Creatine
  • MSTN: Myostatin

myostatin hmb leucine creatine study layout

There were 5 total groups.

  • One group of C2C12 myotubes were exposed to 10 ng/ml myostatin.
  • Three were exposed to 10 ng/ml myostatin plus either 10 µM of either leucine, HMB, or creatine.
  • The last group was a control group exposed to nothing.

The Results

Myostatin caused muscle cells to create less MyoD, but the addition of leucine, HMB, and creatine corrected this. MyoD is an anabolic signal molecule involved in muscle fibre growth. It promotes the recruitment of stem cells to muscle fibres.

Leucine, HMB, and, most significantly, creatine activated the Mighty gene in muscle cells. This gene inhibits the function of myostatin. Akirin-1 is another name for the Mighty gene.

myostatin hmb leucine creatine study results

Myostatin inhibited the production of muscle fibres. Leucine, HMB, and creatine all reduced the inhibitory effect. And the activation of the Mighty gene is largely responsible for this outcome.

The Mighty Gene

Researchers conducted another experiment to see if the Mighty gene is essential for muscular development. They inhibited the Mighty gene this time.

The findings demonstrate that in muscle cells where inhibition of the Mighty gene occurred, fewer muscular fibres were produced than in muscle cells where the Mighty gene was still active.


Leucine, HMB, and creatine monohydrate reverse myostatin-induced atrophy in myotubes, according to this study.

This is most likely due to the independent action of each element on Akirin-1/Mighty mRNA expression.

Furthermore, creatine monohydrate therapy increases Akirin-1/Mighty mRNA expression, resulting in a hypertrophic effect that is not reliant on muscle protein synthesis. Creatine supplementation has also been shown to reduce circulating levels of myostatin. (3)

Researchers are also investigating whether creatine, leucine, and HMB may enhance each other’s myostatin inhibitory effects. When data suggests that leucine and HMB promote muscle development through different mechanisms, this idea becomes more plausible. (2)

Further Reading

> BCAAs (An Overview)

> Creatine (An Overview)

> HMB (An Overview)


Below are definitions and short explanations of what some of the terms in this article mean.

  • Akirin-1/Mighty: Akirin-1 (Mighty) is a downstream target gene of myostatin and has been shown to be a promyogenic factor (promotes muscle growth).
  • mRNA Expression: The amount and type of mRNA molecules in a cell reflect the function of that cell. The more mRNA expression is occurring, the more of an effect will be seen. If there is higher mRNA expression of Akirin-1, the higher the muscle growth (potentially).
  • Atrophy: Atrophy is the progressive degeneration or shrinkage of muscle or nerve tissue.


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This evidence based analysis of the effect of HMB, leucine, and creatine on myostatin features 3 references, listed below.

1. Mobley CB, Fox CD, Ferguson BS, Amin RH, Dalbo VJ, Baier S, Rathmacher JA, Wilson JM, Roberts MD. L-leucine, beta-hydroxy-beta-methylbutyric acid (HMB) and creatine monohydrate prevent myostatin-induced Akirin-1/Mighty mRNA down-regulation and myotube atrophy. J Int Soc Sports Nutr. (2014, Aug 13) ✔

2. Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ. Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism. J Physiol. (2013, Jun 1) ✔

3. Saremi A, Gharakhanloo R, Sharghi S, Gharaati MR, Larijani B, Omidfar K. Effects of oral creatine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrinol. (2010, Apr 12) (Randomised Controlled Trial) ✔

✔ Citations with a tick indicate the information is from a trusted source.

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