Myostatin

A stop lever on muscle protein synthesis with no other known roles in the body, abolishing Myostatin in the body results in excessive muscle growth and a reduction of fat mass; the 'holy grail' of bodybuilding due to its potency, supplements targeting Myostatin are lacklustre.

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BMultiple studies where at least two are double-blind and placebo controlled
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Table of Contents:


Interactions with Skeletal Muscle Mass

According to many researchers, Myostatin is the most potent negative regulator of skeletal muscle mass known to date.[1][2][3] It is expressed almost exclusively in muscle tissue (with some in cardiac tissue).[4] Myostatin has also been found in skin cells.[5] Myostatin can be reduced via various means:

  • Genetic knock-out (taking out or suppressing the gene that codes for Myostatin)
  • Genetic upregulation of antagonists (increasing the activity of a gene that inhibits myostatin activity)
  • Administration of antagonists to a subject

The end result is that when Myostatin is inable to act on its Activin-II receptor, muscle mass is drastically enhanced.[6][7][8][9][10][11][12][13]

The myostatin protein's structure is highly preserved (similar) among species[14], and similar effects of myostatin suppression have been observed in sheep,[15] cattle,[16][17] dogs,[18] fish,[19] primates[20] and there has been a case study of a healthy human with myostatin mutation.[21] It is likely that animal models will apply to humans in a similar manner.


Interactions with Body Fat

In animal models of Myostatin deficiency, less amounts of body fat are routinely observed alongside the increased muscle mass.

This is due indirectly due to the process of building muscle mass being highly endothermic, and requiring energy to be conducted. Myostatin's effects on muscle tissue are what indirectly causes depletion of fat cells through providing energy for protein synthesis.[22][2]

Myostatin deficiency seems to be related to an increased production of brown fat in mouse models, although there may be some species related differences in regards to humans.[23]


Interactions with Glucose Metabolism

Myostatin seems to be able to increase the activity of AMPK, which increase glucose consumption in muscle cells.[24] However, in vivo studies show reduced insulin resistance in periods of Myostatin deficiency. Some implicate AMPK activity upregulated in this scenario as well[25] while other studies suggest that increased energy consumption by muscle tissue, thus depriving fat tissue of anabolism, is the cause for increased insulin sensitivity.[26][27][25] This is shown by myostatin deficiency in muscle, but not fat, resulting in increased insulin sensitivity in mice.[22]

A cause-effect relationship was suggested with a high correlation between reduced myostatin (from aerobic exercise) causing a dose-dependent decrease in insulin resistance, and inducing insulin resistance with myostatin injections.[28]

In addition to increased glucose sensitivity, increased muscular consumption of energy appears to be protective from artherosclerosis.[29]


Inhibiting Myostatin

Myostatin can be inhibited from being produced, can be bound to and sequestered in the blood before it acts on the Activin-II receptor, or the post-receptor cascade can be inhibited. Various methods are available to inhibit myostatin's effects on the cell nucleus, although many are pharmaceutical in nature and not available to the public.

Myostatin Propeptide

Myostatin propeptide is a part of the originally synthesized chain of myostatin that the active component must disassociated with in order to function. In effect, Myostatin Propeptide is one method that can regulate active Myostatin in serum.[30]

Overexpression of Myostatin Propeptide in animals tends to result in increased muscle mass and the other various effects noted in preceding sections.[29][31][32][33][34] Other studies suggest that it carries many of the same benefits seen in Myostatin deficiency, such as enhanced injury recovery rates,[35] It is possible to inject a mutant pro-peptide gene that provides long-term myostatin suppression.[36]

Follistatin and related peptides

Follistatin is a naturally occurring and produced hepatokine (cytokine produced mostly in the liver, although it is produced in limited amounts in many cells) that can bind to and inactivate myostatin in serum. Either manipulating genetic expression of follistatin production or otherwise injecting follistatin appears to produce the same effects as myostatin deficiency.[7]

Follistatin also has the ability to bind to other serum factors, one of which is Activin. Since activin also partially inhibits protein synthesis, suppressing both myostatin and activin can result in further increased muscle growth.[37][38] This is shown in one study where follistatin administration to myostatin deficienct mice resulted in even further muscle growth.[39]

However, activins also mediate the growth and proliferation of other cells rather than just skeletal muscle.[40] Due to this reason, a myostatin-specific peptide has been derived from follistatin and dubbed 'Follistatin Derived Peptide II', and shows promise in inhibiting myostatin without influencing other serum factors.[41][8]

Decorin

Decorin is a relatively small protein composed of dermatin/chondroitin sulfate chain. It is able to modulate myostatin's effects on muscle by binding to it in serum.[42][43][44][45] In the lifecycle, decorin and myostatin seem to be highly correlated in their expression.[46]

Decorin also seems to be able to upregulate levels of follistatin.[43]

Vaccination

A Myostatin 'vaccination' has been developed in culture from yeast, where oral and intravenous administration to mice appears to create Myostatin-specific antibodies and enhance muscular phenotype as a result.[6]

Possible side-effects of inhibiting Myostatin

Myostatin's effects on negative regulation (and thus acceleration of protein synthesis when inhibited) are localized to skeletal muscle and cardiac tissue.[47] However, in an animal model looking at cardiac growth in aging mice, it was not observed despite beneficial metabolic effects of Myostatin being noted.[48]

As myostatin is located in the skin, myostatin null mice seem to have a rise in the protein Decorin, which delays skin healing via suppressing TGF-b proteins.[5]


Myostatin and Lifestyle

Exercise

Acute resistance exercise seems to, on average, decrease myostatin content in serum.[49][50][51] Training adaptations over time increase myostatin mRNA and protein content on average.[52] One study did note a decrease in Myostatin,[53] but it was mentioned it may be due to how they analyzed myostatin content.[54] The increase in myostatin over time appears to be a by-product of enhanced ribosomal density, and increased protein synthesis capabilities in total (as myostatin is a protein).

In mice, periods of unloading do not seem to increase myostatin although stressing a muscle with mechanical loading after time off causes a decrease in myostatin.[55] These results may be due to starting the study with deloading, as human studies suggest that deloading after training causes an increase in Myostatin.[56] Similar unloading protocols in humans see the same rise in Myostatin levels[57] and can rise in as short as three days.[58]

Aerboic exercise has also been implicated in reducing myostatin content in serum.[28]

A study in mice suggest that myostatin inhibition alone has no effect on increasing strength while it increases muscle mass, but inhibiting NF-kB alongside myostatin inhibition alleviates this.[59]

Even in consideration to all the above, exercise-mediated changes in myostatin do not appear to be related to actual muscle growth.[53] Myogenic factors that myostatin suppresses are related,[60] but not myostatin per se.

Diet

Treatment of myotubes with Vitamin D seems to suppress myostatin levels, possibly through an increase in follistatin.[61]

Temperature

In animals, there is a known phenomena where cold exposure increases skeletal weight in finches,[62] ducks,[63] chicks,[64] and chickadees.[65]

At least one study (in chicks) using Cold Exposure at 4°C (relative to 30°C control conditions) for 24 hours reported a reduction in myostatin mRNA, although prolonged exposure for eight days was not associated with any alterations in myostatin mRNA content.[64]

Cold exposure has been linked to increasing myostatin, but oddly all relevant research is conducted in birds. Application of this information towards mammalian species is not known and preliminary

Aging

In mice, Myostatin appears to slowly rise after youth but then plateau.[55] This increase may be implicated in losing an ability to gain muscle mass as easily after youth, but does not appear to significantly influence sarcopenia.

In humans, this increased amount of myostatin in aged individuals is met with greater suppression of myostatin from exericse.[66]

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