Myostatin, or growth differentiation factor 8, is produced in skeletal muscle and acts as a negative regulator of muscle fiber count and size, maintaining a balance in muscular development. Myostatin has been shown, primarily in animals, to be a protein that inhibits muscle growth. However it is very likely that its level of inhibition is far less in humans (meaning it is not a huge inhibitor of muscle growth in humans) – which we’ll explore later.

Follistatin opposes myostatin by binding to it and inhibiting its suppressive effects on muscle growth. Elevated follistatin levels can increase muscle mass and improve tissue regeneration.

It has been theorised why Anabolic Steroids produce less muscle growth over time as they may increase Myostatin levels. 

However, studies show conflicting results.

In a study titled ‘Time course of changes in growth factor mRNA levels in muscle of steroid-implanted and nonimplanted steers’ researchers found that trenbolone acetate implants did not affect myostatin levels in the skeletal muscles of steers.

In a study titled ‘Nandrolone Normalizes Determinants of Muscle Mass and Fiber Type after Spinal Cord Injury’ researchers noted that “The mRNA levels for myostatin were not altered in muscle after SCI and were unaffected by testosterone or nandrolone administration”

A study (titled: ‘Frequent sequence variation in the human myostatin (GDF8) gene as a marker for analysis of muscle-related phenotypes’) on the impact of MSTN gene mutations on bodybuilding progress (study included five Mr. Olympia contenders and several other top-tier IFBB pros) found that there was no significant relationship between these mutations and overall muscle mass response to strength training. Clearly, Myostatin is a very limited factor in muscle growth.

What many fail to consider is that resistance training itself reduces myostatin levels. A 2023 meta-analysis titled ‘The effects of resistance training on myostatin and follistatin in adults: A systematic review and meta-analysis’ concluded that “Resistance training in adults is effective for reducing myostatin”.

The reason I mention this is because even if Steroids did increase myostatin levels, simply engaging in resistance training would simply offset this. Heavy resistance training is well-documented to reduce myostatin levels. Studies show a reduction in myostatin expression after strength-specific training. ALSO the reduction of myostatin after exercise appears to be load-dependent, meaning heavier weights lead to a greater decrease in myostatin levels.

Myostatin inhibitors notoriously failed to reach efficacy in humans. Although they had significant effects on muscle mass of mice, creating ‘mighty mice’, they have essentially been abandoned for further research in humans due to their lack of efficacy. This was explained well in the review paper below.

Essentially the reasons Myostatin inhibitors failed to work in humans comes down to differences in our genetics compared to rodents.

• Differences in myostatin levels: Mice have ~10-fold higher circulating myostatin levels than humans. Also, myostatin repression is ~3-fold higher in mice. More myostatin repressor activity is needed to constrain muscle mass in mice compared to humans.
• Mice have remarkably longer telomeres, which do not substantially shorten through replication and aging, suggesting a greater comparative capacity for satellite cell activity-mediated regeneration and muscle growth
• Myostatin inhibition causes type II fiber phenotype shifts and changes to metabolism, which in dystrophic muscle prevents functional gains. However this may not be relevant to those without Duchenne Muscular Dystrophy.

Save your money on myostatin inhibitors: Here are some easy ways to lower myostatin levels if your still not convinced.

• Lifting heavy weights is known to lower myostatin levels. Research shows that strength training reduces myostatin expression. Plus, the drop in myostatin depends on the weight used – heavier loads lead to a bigger decrease.
• Research suggests estradiol can suppress myostatin gene expression, leading to lower myostatin levels in the bloodstream. ALSO Estradiol can increase insulin-like growth factor 1 (IGF-1) which indirectly lowers myostatin levels, and improves muscle gains. 
• Vitamin D and its metabolites, along with Epicatechin, have been shown to reduce myostatin levels and increase follistatin levels in human subjects and animal models.

Refrences:

Wu Y, Zhao J, Zhao W, Pan J, Bauman WA, Cardozo CP. Nandrolone normalizes determinants of muscle mass and fiber type after spinal cord injury. J Neurotrauma. 2012 May 20;29(8):1663-75. doi: 10.1089/neu.2011.2203. Epub 2012 Apr 16. PMID: 22208735; PMCID: PMC5364642.

 Pampusch MS, Johnson BJ, White ME, Hathaway MR, Dunn JD, Waylan AT, Dayton WR. Time course of changes in growth factor mRNA levels in muscle of steroid-implanted and nonimplanted steers. J Anim Sci. 2003 Nov;81(11):2733-40. doi: 10.2527/2003.81112733x. PMID: 14601876.

Rybalka, E.; Timpani, C.A.; Debruin, D.A.; Bagaric, R.M.; Campelj, D.G.; Hayes, A. The Failed Clinical Story of Myostatin Inhibitors against Duchenne Muscular Dystrophy: Exploring the Biology behind the Battle. Cells 2020, 9, 2657. https://doi.org/10.3390/cells9122657

Ferrell RE, Conte V, Lawrence EC, Roth SM, Hagberg JM, Hurley BF. Frequent sequence variation in the human myostatin (GDF8) gene as a marker for analysis of muscle-related phenotypes. Genomics. 1999 Dec 1;62(2):203-7. doi: 10.1006/geno.1999.5984. PMID: 10610713.