Myostatin Inhibition: What Is It, How It Works & Should You?

yostatin, a member of the transforming growth factor-beta (TGF-β) superfamily, is a protein that has been identified as a critical regulator of skeletal muscle mass.

Discovered in the 1990s, it's primarily produced in skeletal muscle cells and acts as a negative (catabolic) regulator of muscle growth.

Myostatin functions by inhibiting the differentiation and proliferation of myoblasts, which are precursor cells to muscle fibers.

Its role is crucial in maintaining muscle size and function, preventing excessive muscle growth that could be metabolically taxing and biomechanically disadvantageous.

Role of Myostatin in Muscle

The role of myostatin in muscle regulation is multifaceted.

It is not only involved in the inhibition of muscle growth but also plays a role in muscle wasting conditions, such as cachexia, sarcopenia, and muscular dystrophies.

Myostatin signaling involves a cascade of molecular interactions that ultimately lead to the inhibition of muscle cell growth and differentiation.

This is achieved by the binding of myostatin to specific receptors on muscle cells, activating a signaling pathway that results in the downregulation of genes responsible for muscle growth and upregulation of genes that inhibit it.

Research has shown that natural mutations or deletions in the myostatin gene in some animals, including certain breeds of cattle and dogs, lead to a dramatic increase in muscle mass.

These observations have highlighted the potential of targeting myostatin for therapeutic purposes, particularly in conditions characterized by muscle wasting.

Concept of Myostatin Inhibition

The concept of myostatin inhibition revolves around the idea of blocking or reducing the activity of myostatin to promote muscle growth.

This can be achieved through various methods, including the use of myostatin-inhibiting drugs, proteins, antibodies, or small molecules that interfere with its signaling pathway.

Myostatin inhibitors have the potential to serve as therapeutic agents for a range of conditions where muscle loss or weakness is a concern.

This includes:

• muscular dystrophies

• age-related muscle loss (sarcopenia)

• wasting diseases such as cancer cachexia

In addition to medical applications, there is interest in the potential use of myostatin inhibitors in enhancing livestock muscle yield and even in sports, where muscle strength and size are advantageous, although this raises ethical and regulatory concerns.

Myostatin plays a vital role in regulating muscle mass and function.

Myostatin inhibitors are a promising approach to treat muscle wasting diseases and improve muscle function in various pathological conditions.

However, the long-term effects and safety of myostatin inhibitors need to be thoroughly studied and understood.

What Does Myostatin Inhibition Do?

The inhibition of myostatin, a key regulator of muscle mass, has many implications for muscle development, regeneration, and overall body composition.

1. May Prevent Muscle Degeneration

• Muscular Dystrophies: In diseases like muscular dystrophies, myostatin inhibition may be beneficial. By reducing the myostatin activity, muscle wasting can potentially be slowed or even reversed. This could improve muscle strength and quality of life.

• Age-Related Muscle Loss (Sarcopenia): As people age, they naturally lose muscle mass, a condition known as sarcopenia. Myostatin inhibition could counteract this process by promoting muscle growth, enhancing mobility and reducing the risk of falls and fractures in the elderly.

• Cachexia: Conditions like cancer, chronic kidney disease, and heart failure often lead to cachexia, a severe form of muscle wasting. Inhibiting myostatin could be a strategy to combat this, improving outcomes.

2. May Help Build Muscle

• Muscle Hypertrophy: Myostatin naturally limits muscle growth. Inhibiting it could lead to muscle hypertrophy (increased muscle size), which might be beneficial in various contexts, from sports and fitness to rehabilitation from injuries.

• Improved Muscle Repair: Myostatin inhibition could enhance the body's ability to repair and regenerate muscle tissue following injury. This is particularly relevant for athletes and individuals undergoing physical rehabilitation.

3. May Reduce Fat

• Body Composition: By promoting muscle growth, myostatin inhibition may indirectly lead to reduced fat accumulation. Muscles are metabolically active tissues; this means an increase in muscle mass could enhance basal metabolic rate, leading to higher calorie expenditure.

• Obesity: Reduced myostatin could have implications for the treatment of obesity. By enhancing muscle mass and metabolic rate, it may help in weight management.

4. Improved Metabolic Function

The reduction in fat gain is not only a result of increased muscle mass but also involves complex interactions with metabolic pathways.

Myostatin inhibition might influence fat metabolism, skeletal muscle metabolism, insulin sensitivity, and other metabolic pathways, which are all crucial factors in overall metabolic health.

5. Potential Therapeutic Applications

Beyond muscle diseases, myostatin inhibitors could potentially aid in recovery from surgeries or conditions where muscle atrophy occurs due to immobilisation, such as bed-rest.

For example, patients with conditions such as amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy, and multiple sclerosis often exhibit markedly elevated myostatin levels, a common factor in the substantial muscle loss characteristic of these diseases.

Consequently, research into myostatin inhibition is gaining momentum as a promising strategy to combat muscle degradation in these conditions.

In a significant development, the FDA has awarded Orphan Drug Status to SRK-015, a drug designed to inhibit myostatin, specifically targeting spinal muscular atrophy.

Mechanism of Myostatin

Myostatin is produced in skeletal muscle cells as a precursor molecule.

This precursor is processed to release a mature, active form of myostatin that can bind to receptors on muscle cells.

Receptor Binding and Signalling

The active myostatin binds to specific receptors on muscle cells, primarily the Activin Type II receptors (ActRIIA and ActRIIB).

These receptors are part of the TGF-β receptor superfamily and are essential for myostatin signaling.

This binding triggers a cascade of intracellular signaling, mainly through the Smad pathway, leading to the inhibition of muscle cell growth and differentiation.

Smad is a classical pathway for TGF-β family signaling. The binding initiates the phosphorylation of Smad2 and Smad3 proteins, which then form a complex with Smad4.

This complex translocates to the nucleus, where it regulates the transcription of target genes involved in muscle growth inhibition.

Regulation by Binding Proteins

Naturally occurring binding proteins, such as follistatin, myostatin propeptide, and others, can regulate myostatin activity by binding to it and preventing its interaction with muscle cell receptors.

How Myostatin Inhibitors Work

There are many types of myostatin inhibitors being researched and studied, they all work on at least one of these pathways (except for gene editing strategies).

1. Interference with Receptor Binding: Myostatin inhibitors function primarily by preventing myostatin from binding to its receptors on muscle cells. This can be achieved either by directly binding to myostatin or by interacting with its receptors.

2. Alteration of Signaling Pathways: Some inhibitors may also work by interfering with the downstream signaling pathways activated by myostatin, such as the Smad pathway, thus preventing the transcriptional effects that lead to muscle growth inhibition.

3. Affecting Natural Regulation: Another mechanism involves augmenting the activity of natural myostatin-binding proteins, thereby increasing their ability to neutralize myostatin.

The mechanism of myostatin inhibition involves a complex interplay of molecular interactions, targeting myostatin itself, its receptors, and the signaling pathways it activates.

Types of Inhibitors

The development of various types of myostatin inhibitors, each with its unique mode of action, offers a range of therapeutic possibilities.

There are various types of myostatin inhibitors being developed, explained below.

1. Antibodies

Antibodies designed to target myostatin can bind to it directly, neutralizing its activity.

These antibodies are highly specific and can effectively reduce the amount of active myostatin available to bind to muscle cell receptors.

Due to their stability and long half-life in the bloodstream, antibody-based inhibitors can provide sustained myostatin inhibition.

2. Propeptides

The propeptide part of the myostatin precursor molecule, even after myostatin is activated, can still bind to and inhibit the mature myostatin.

This is a natural regulatory mechanism that can be harnessed therapeutically.

By binding to myostatin, propeptides prevent it from interacting with its receptors on cells, thereby inhibiting its muscle growth-suppressing effects.

Other Pharmacological Agents

There are also some unique agents and techniques currently in development, such as the following.

1. Small Molecule Inhibitors: These are compounds that can interfere with the myostatin signaling pathway at various points, such as receptor binding or signal transduction. Their smaller size compared to antibodies or propeptides can offer advantages in terms of delivery and distribution within the body.

2. Gene Editing Technologies: Techniques like CRISPR-Cas9 could be used to disrupt the myostatin gene or its receptors, providing a more permanent solution to inhibit myostatin's effects.

3. Modulators of Related Pathways: Some agents may work by modulating other growth factors or signaling pathways that interact with or counteract myostatin's effects, providing a more holistic approach to muscle regulation.

Supplements that may Reduce Myostatin

Although reducing myostatin may be a long way off in terms of therapeutics, there are still some supplements that could help.

1. Creatine

Creatine is well-known for its role in enhancing muscle strength and size.

While primarily recognized for its ability to regenerate ATP during high-intensity activities, it may also have an indirect role in myostatin regulation. (8)

Some studies suggest that creatine supplementation could influence myostatin levels.

The mechanism behind this is not fully understood but may relate to creatine’s effect on muscle fiber growth and satellite cell proliferation, which could in turn impact myostatin expression.

Research in this area is ongoing, and while some studies indicate a potential link between creatine use and reduced myostatin levels, conclusive evidence is still needed.

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2. Epicatechin

Epicatechin is a flavonol found in dark chocolate and green tea. It has gained attention for its potential health benefits, including cardiovascular health and muscle growth.

Epicatechin is thought to inhibit myostatin by promoting the release of follistatin, a myostatin-binding protein. (6)

Increased follistatin levels can reduce the effects of myostatin, potentially leading to muscle growth.

However, the evidence supporting epicatechin's role in myostatin inhibition primarily comes from animal studies and limited human trials.

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3. Sulforaphane

Sulforaphane, found in broccoli, has strong antioxidant properties and potential effects on muscle hypertrophy and health.

It may also have a role to play in the context of myostatin reduction and muscle health. (7)

However, more research is needed to fully understand its impact on myostatin and the practical implications for muscle growth and maintenance in humans.

A diet rich in cruciferous vegetables, as a source of sulforaphane and other beneficial compounds, can be part of a healthy lifestyle supporting overall muscle health.

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Foods that Promote Myostatin Inhibition

There are also some foods that may reduce myostatin.

1. Protein-Rich Foods: While direct evidence linking specific foods to myostatin inhibition is limited, diets rich in high-quality protein (from sources like lean meats, fish, eggs, and dairy products) are essential for muscle growth and repair.

2. Foods with Flavonoids: Foods high in flavonoids, such as berries, green tea, and dark chocolate (rich in epicatechin), might play a role in modulating myostatin levels, given their impact on overall muscle health and potential to increase follistatin levels.

3. Omega-3 Fatty Acids: Found in fish and some plant oils, omega-3 fatty acids are known for their anti-inflammatory properties. There is emerging evidence suggesting they may also play a role in muscle health, possibly influencing myostatin expression, although the exact mechanism and extent of this effect are still under investigation.

Safety Profile and Side Effects

One of the primary concerns with myostatin inhibitors is the limited long-term research, particularly in humans.

While animal studies provide valuable insights, they may not fully predict the human response, especially over extended periods.

1. Increased Risk of Injury

Excessive muscle growth, without corresponding increases in the strength of tendons and ligaments, could lead to a higher risk of musculoskeletal injuries.

This imbalance might make individuals more susceptible to strains and sprains.

2. Tendon Rupture

There's a potential risk of tendon rupture with myostatin inhibition.

Muscles may grow stronger and larger rapidly, but tendons might not adapt at the same rate, leading to an increased risk of rupture under stress.

There may also be a link between lower myostatin and weaker tendons too.

3. Heart Failure

The impact of myostatin inhibitors on cardiac muscle is a significant concern.

Since the heart is also a muscle, unchecked growth or changes in cardiac muscle structure could potentially lead to heart failure or other cardiovascular issues.

Another concern could be higher blood pressure, changes to blood vessels, cholesterol, and an increase in blood volume and body weight could also negatively affect the heart and circulatory system.

4. Other Side Effects

Other possible side effects might include metabolic imbalances, changes in blood sugar levels, and effects on other organ systems.

The broad role of myostatin in the body means that its inhibition could have wide-ranging and currently unpredictable effects.

Ethical Implications in Sports and PEDs

The use of myostatin inhibitors in sports raises ethical concerns similar to those associated with steroids and other performance-enhancing drugs.

Although some myostatin inhibitors, such as follistatin, ACE-031, etc are already freely available to buy as research chemicals.

Conclusion

The exploration of myostatin inhibition offers a compelling glimpse into the future of treating muscle-wasting diseases and enhancing muscle function.

The potential of myostatin inhibitors, from antibodies and propeptides to pharmacological agents, opens up new avenues for therapeutic interventions in conditions like muscular dystrophy, sarcopenia, and cachexia.

The emerging interest in natural inhibitors found in foods and supplements, such as creatine, epicatechin, and sulforaphane, further expands the possibilities in this field.

References

1. Double muscling in cattle due to mutations in the myostatin gene

2. Tendons of myostatin-deficient mice are small, brittle, and hypocellular

3. Grobet L, Pirottin D, Farnir F, Poncelet D, Royo LJ, Brouwers B, Christians E, Desmecht D, Coignoul F, Kahn R, Georges M. Modulating skeletal muscle mass by postnatal, muscle-specific inactivation of the myostatin gene. Genesis. 2003 Apr;35(4):227-38. doi: 10.1002/gene.10188. PMID: 12717734.

4. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997 May 1;387(6628):83-90. doi: 10.1038/387083a0. PMID: 9139826.

5. Dalbo VJ, Roberts MD, Sunderland KL, Poole CN, Stout JR, Beck TW, Bemben M, Kerksick CM. Acute loading and aging effects on myostatin pathway biomarkers in human skeletal muscle after three sequential bouts of resistance exercise. J Gerontol A Biol Sci Med Sci. 2011 Aug;66(8):855-65. doi: 10.1093/gerona/glr091. Epub 2011 Jun 10. PMID: 21665986.

6. Gutierrez-Salmean G, Ciaraldi TP, Nogueira L, Barboza J, Taub PR, Hogan MC, Henry RR, Meaney E, Villarreal F, Ceballos G, Ramirez-Sanchez I. Effects of (-)-epicatechin on molecular modulators of skeletal muscle growth and differentiation. J Nutr Biochem. 2014 Jan;25(1):91-4. doi: 10.1016/j.jnutbio.2013.09.007. Epub 2013 Oct 18. PMID: 24314870; PMCID: PMC3857584.

7. Fan H, Zhang R, Tesfaye D, Tholen E, Looft C, Hölker M, Schellander K, Cinar MU. Sulforaphane causes a major epigenetic repression of myostatin in porcine satellite cells. Epigenetics. 2012 Dec 1;7(12):1379-90. doi: 10.4161/epi.22609. Epub 2012 Oct 23. PMID: 23092945; PMCID: PMC3528693.

8. 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;317(1-2):25-30. doi: 10.1016/j.mce.2009.12.019. Epub 2009 Dec 22. PMID: 20026378.