Myostatin
Encyclopedia
Myostatin is a secreted TGF beta
protein
family member that inhibits muscle
differentiation and growth. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood and acts on muscle tissue, by binding a cell-bound receptor
called the activin type II receptor
. In humans, myostatin is encoded by the MSTN gene
.
Animals lacking myostatin or animals treated with substances such as follistatin
that block the binding of myostatin to its receptor have significantly larger muscles.
encoding myostatin was discovered in 1997 by geneticists Alexandra McPherron and Se-Jin Lee who also produced a strain of mutant mice that lack the gene. These myostatin "knockout" mice have approximately twice as much muscle as normal mice. These mice were subsequently named "mighty mice".
Naturally occurring myostatin "nulls" have been identified in cattle, whippet
s, and humans; in each case the result is a dramatic increase in muscle mass. A mutation in the 3' UTR
of the myostatin gene in Texel sheep
creates target sites for the microRNAs miR-1
and miR-206. This is likely to cause the muscular phenotype of this breed of sheep.
sequence of a myostatin gene in two breeds of cattle Belgian Blue
and Piedmontese
, and found that these animals have mutations in that myostatin gene (various mutations in each breed) which in one way or another lead to absence of functional myostatin. Unlike mice with a damaged myostatin gene, in these cattle breeds the muscle cells multiply rather than enlarge. People describe these cattle breeds as "double muscled", but the total increase in all muscles is no more than 40%.
. This protein normally restrains muscle growth, ensuring that muscles do not grow too large. Mutations that reduce the production of functional myostatin lead to an overgrowth of muscle tissue. Myostatin-related muscle hypertrophy has a pattern of inheritance known as incomplete autosomal dominance. People with a mutation in both copies of the MSTN gene in each cell
(homozygotes) have significantly increased muscle mass and strength. People with a mutation in one copy of the MSTN gene in each cell (heterozygotes) also have increased muscle bulk, but to a lesser degree.
In 2004, a German
boy was diagnosed with a mutation in both copies of the myostatin-producing gene, making him considerably stronger than his peers. His mother, a former sprinter, has a mutation in one copy of the gene.
An American boy born in 2005 (Liam Hoekstra) was diagnosed with a clinically similar condition but with a somewhat different cause: his body produces a normal level of functional myostatin, but because he is stronger and more muscular than most others his age, his doctor believes that a defect in his myostatin receptors prevents his muscle cells from responding normally to myostatin. Liam appeared on the television show World's Strongest Toddler.
A 2007 NIH study in PLOS Genetics found a significant relationship in whippet
s between a myostatin mutation and racing performance. Whippets that were heterozygous for a 2 base pair deletion in the myostatin gene were significantly over-represented in the top racing classes. The mutation resulted in a truncated myostatin protein
, likely resulting in an inactive form of myostatin.
Whippet
s with a homozygous deletion were apparently less able runners although their overall appearance was significantly more muscular. Whippets with the homozygous deletion also had an unusual body shape, with a broader head, pronounced overbite, shorter legs, and thicker tails. These whippets have also been called "bully whippets" by the breeding community due to their size. Despite the name "bully", these dogs tend have a friendly and positive demenour towards people as usual for whippets.
This particular mutation was not found in other muscular dog breeds such as boxers
and mastiff
s, nor was it found in other sighthound
s such as greyhound
s, Italian greyhound
s, or Afghan hound
s. The authors of the study suggest that myostatin mutation may not be desirable in greyhounds, the whippets' nearest relative, because greyhound racing requires more significant endurance due to the longer races (900 meters for greyhounds vs. 300 meters for whippets).
of proteins.
Human myostatin consists of two identical subunits, each consisting of 109 amino acid
residues. Its total molecular weight
is 25.0 kDa
. The protein is made in an inactive form. For it to be activated, a protease
cleaves the NH2-terminal, or "pro-domain" portion of the molecule, resulting in the now-active COOH-terminal dimer.
Myostatin binds to the activin type II receptor
, resulting in a recruitment of a coreceptor called Alk-3
or Alk-4
. This coreceptor then initiates a cell signaling
cascade in the muscle
, which includes the activation of transcription factor
s in the SMAD
family - SMAD2 and SMAD3. These factors then induce myostatin-specific gene regulation
. When applied to myoblasts, myostatin inhibits their differentiation
into mature muscle fibers.
Recently, myostatin has also been shown to inhibit Akt
, a kinase that is sufficient to cause muscle hypertrophy
, in part through the activation of protein synthesis
.
Therefore, myostatin acts in two ways, by inhibiting muscle
differentiation
and by inhibiting Akt-induced protein synthesis.
. The idea is to introduce substances that block myostatin. In 2002, researchers at the University of Pennsylvania
showed that monoclonal antibody specific to myostatin improves the condition of mice with muscular dystrophy, it is presumed, by blocking myostatin's action. Similar results in monkeys were published in 2009.
In 2005, Lee showed that a two-week treatment of normal mice with soluble activin type IIB receptor, a molecule that is normally attached to cells and binds to myostatin, leads to a significantly increased muscle mass (up to 60%). It is thought that binding of myostatin to the soluble activin receptor prevents it from interacting with the cell-bound receptors.
It remains unclear as to whether long-term treatment of muscular dystrophy with myostatin inhibitors is beneficial: The depletion of muscle stem cell
s could worsen the disease later on.
, no myostatin-inhibiting drugs for humans are on the market, but an antibody genetically engineered to neutralize myostatin was developed by New Jersey pharmaceutical company Wyeth
. The inhibitor is called MYO-029, but, after an initial clinical trial, Wyeth says they will not be developing the drug. Some athletes, eager to get their hands on such drugs, turn to the internet, where fake "myostatin blockers" are being sold.
Myostatin levels are effectively decreased by creatine
supplementation.
A technique for detecting mutations in myostatin variants has been developed.
In the Japanese manga
Air Gear
, the two characters Akira Udou and Mitsuru Bandou have this condition.
TGF beta
Transforming growth factor beta is a protein that controls proliferation, cellular differentiation, and other functions in most cells. It plays a role in immunity, cancer, heart disease, diabetes, Marfan syndrome, and Loeys–Dietz syndrome....
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
family member that inhibits muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
differentiation and growth. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood and acts on muscle tissue, by binding a cell-bound receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
called the activin type II receptor
Activin type 2 receptors
The Activin type 2 receptors modulate signals for ligands belonging to the Transforming growth factor beta superfamily of ligands. These include: Activin , Bone morphogenetic proteins and Nodal. They are involved in a host of physiological processes including, growth, cell differentiation,...
. In humans, myostatin is encoded by the MSTN gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Animals lacking myostatin or animals treated with substances such as follistatin
Follistatin
Follistatin also known as activin-binding protein is a protein that in humans is encoded by the FST gene. Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals....
that block the binding of myostatin to its receptor have significantly larger muscles.
Discovery and sequencing
The geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
encoding myostatin was discovered in 1997 by geneticists Alexandra McPherron and Se-Jin Lee who also produced a strain of mutant mice that lack the gene. These myostatin "knockout" mice have approximately twice as much muscle as normal mice. These mice were subsequently named "mighty mice".
Naturally occurring myostatin "nulls" have been identified in cattle, whippet
Whippet
The Whippet is a breed of dog in the sighthound family. They are active and playful and are physically similar to a small Greyhound.- Description :...
s, and humans; in each case the result is a dramatic increase in muscle mass. A mutation in the 3' UTR
Three prime untranslated region
In molecular genetics, the three prime untranslated region is a particular section of messenger RNA . It is preceeded by the coding region....
of the myostatin gene in Texel sheep
Texel (sheep)
The Texel is a breed of domestic sheep originally from the island of Texel in the Netherlands. It is now a popular lean meat sheep in the USA, Australia, New Zealand, Uruguay and Europe. The Texel is a heavily muscled sheep. It produces a lean meat carcass and will pass on this quality to crossbred...
creates target sites for the microRNAs miR-1
Mir-1 microRNA precursor family
The miR-1 microRNA precursor is a small micro RNA that regulates its target protein's expression in the cell. microRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide products. In this case the mature sequence comes from the 3'...
and miR-206. This is likely to cause the muscular phenotype of this breed of sheep.
Effects of inactivated myostatin in cattle
After that discovery, several laboratories cloned and established the nucleotideNucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
sequence of a myostatin gene in two breeds of cattle Belgian Blue
Belgian Blue
thumb|right|Belgian Blue bullthumb|right|Belgium Blue cow with the scars from [[caesarean sections]] clearly visible.Belgian Blue cattle are a beef breed from Belgium, known in French as . Alternative names include Belgian Blue-White, Belgian White and Blue Pied, Belgian White Blue, Blue and Blue...
and Piedmontese
Piedmontese (cattle)
thumb|230px|A Piedmontese bullThe Piedmontese is a breed of cattle from the region of Piedmont, in north-west Italy. The calves are born fawn in colour, turning grey-white as they mature....
, and found that these animals have mutations in that myostatin gene (various mutations in each breed) which in one way or another lead to absence of functional myostatin. Unlike mice with a damaged myostatin gene, in these cattle breeds the muscle cells multiply rather than enlarge. People describe these cattle breeds as "double muscled", but the total increase in all muscles is no more than 40%.
The double-muscle mutation in humans
Myostatin is active in muscles used for movement (skeletal muscles) both before and after birthBirth
Birth is the act or process of bearing or bringing forth offspring. The offspring is brought forth from the mother. The time of human birth is defined as the time at which the fetus comes out of the mother's womb into the world...
. This protein normally restrains muscle growth, ensuring that muscles do not grow too large. Mutations that reduce the production of functional myostatin lead to an overgrowth of muscle tissue. Myostatin-related muscle hypertrophy has a pattern of inheritance known as incomplete autosomal dominance. People with a mutation in both copies of the MSTN gene in each cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
(homozygotes) have significantly increased muscle mass and strength. People with a mutation in one copy of the MSTN gene in each cell (heterozygotes) also have increased muscle bulk, but to a lesser degree.
In 2004, a German
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
boy was diagnosed with a mutation in both copies of the myostatin-producing gene, making him considerably stronger than his peers. His mother, a former sprinter, has a mutation in one copy of the gene.
An American boy born in 2005 (Liam Hoekstra) was diagnosed with a clinically similar condition but with a somewhat different cause: his body produces a normal level of functional myostatin, but because he is stronger and more muscular than most others his age, his doctor believes that a defect in his myostatin receptors prevents his muscle cells from responding normally to myostatin. Liam appeared on the television show World's Strongest Toddler.
Performance enhancement in dogs
Whippet
The Whippet is a breed of dog in the sighthound family. They are active and playful and are physically similar to a small Greyhound.- Description :...
s between a myostatin mutation and racing performance. Whippets that were heterozygous for a 2 base pair deletion in the myostatin gene were significantly over-represented in the top racing classes. The mutation resulted in a truncated myostatin protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, likely resulting in an inactive form of myostatin.
Whippet
Whippet
The Whippet is a breed of dog in the sighthound family. They are active and playful and are physically similar to a small Greyhound.- Description :...
s with a homozygous deletion were apparently less able runners although their overall appearance was significantly more muscular. Whippets with the homozygous deletion also had an unusual body shape, with a broader head, pronounced overbite, shorter legs, and thicker tails. These whippets have also been called "bully whippets" by the breeding community due to their size. Despite the name "bully", these dogs tend have a friendly and positive demenour towards people as usual for whippets.
This particular mutation was not found in other muscular dog breeds such as boxers
Boxer (dog)
Developed in Germany, the Boxer is a breed of stocky, medium-sized, short-haired dog. The coat is smooth and fawn or brindled, with or without white markings. Boxers are brachycephalic , and have a square muzzle, mandibular prognathism , very strong jaws and a powerful bite ideal for hanging on to...
and mastiff
English Mastiff
The English Mastiff, referred to by virtually all Kennel Clubs simply as the Mastiff, is a breed of large dog perhaps descended from the ancient Alaunt through the Pugnaces Britanniae. Distinguishable by enormous size, massive head, and a limited range of colors, but always displaying a black mask,...
s, nor was it found in other sighthound
Sighthound
Sighthounds, also called gazehounds, are hounds that primarily hunt by speed and sight, instead of by scent and endurance as scent hounds do.-Appearance:...
s such as greyhound
Greyhound
The Greyhound is a breed of sighthound that has been primarily bred for coursing game and racing, and the breed has also recently seen a resurgence in its popularity as a pedigree show dog and family pet. It is a gentle and intelligent breed...
s, Italian greyhound
Italian Greyhound
The Italian Greyhound is a small breed of dog of the sight hound type, sometimes called an "I.G.", or "Iggy" for short.-Appearance:The Italian Greyhound is the smallest of the sighthounds, typically weighing about and standing about tall at the withers...
s, or Afghan hound
Afghan Hound
The Afghan Hound is one of the oldest sighthound dog breeds. Distinguished by its thick, fine, silky coat and its tail with a ring curl at the end, the breed acquired its unique features in the cold mountains of Afghanistan, where it was originally used to hunt hares and gazelles by coursing them....
s. The authors of the study suggest that myostatin mutation may not be desirable in greyhounds, the whippets' nearest relative, because greyhound racing requires more significant endurance due to the longer races (900 meters for greyhounds vs. 300 meters for whippets).
Biochemistry
Myostatin is a member of the TGF beta superfamilyTransforming growth factor beta superfamily
The transforming growth factor beta superfamily is a large family of structurally related cell regulatory proteins that was named after its first member, TGF-β1, originally described in 1983....
of proteins.
Human myostatin consists of two identical subunits, each consisting of 109 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues. Its total molecular weight
Molecular mass
The molecular mass of a substance is the mass of one molecule of that substance, in unified atomic mass unit u...
is 25.0 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
. The protein is made in an inactive form. For it to be activated, a protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
cleaves the NH2-terminal, or "pro-domain" portion of the molecule, resulting in the now-active COOH-terminal dimer.
Myostatin binds to the activin type II receptor
Activin type 2 receptors
The Activin type 2 receptors modulate signals for ligands belonging to the Transforming growth factor beta superfamily of ligands. These include: Activin , Bone morphogenetic proteins and Nodal. They are involved in a host of physiological processes including, growth, cell differentiation,...
, resulting in a recruitment of a coreceptor called Alk-3
BMPR1A
The bone morphogenetic protein receptor, type IA also known as BMPR1A is a protein which in humans is encoded by the BMPR1A gene. BMPR1A has also been designated as CD292 .- Function :...
or Alk-4
ACVR1B
Activin receptor type-1B is a protein that in humans is encoded by the ACVR1B gene.ACVR1B or ALK-4 acts as a transducer of activin or activin like ligands signals. Activin binds to either ACVR2A or ACVR2B and then forms a complex with ACVR1B. These go on to recruit the R-SMADs SMAD2 or SMAD3...
. This coreceptor then initiates a cell signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
cascade in the muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
, which includes the activation of transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s in the SMAD
SMAD (protein)
SMADs are intracellular proteins that transduce extracellular signals from transforming growth factor beta ligands to the nucleus where they activate downstream TGF-β gene transcription....
family - SMAD2 and SMAD3. These factors then induce myostatin-specific gene regulation
Regulation of gene expression
Gene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene modulation.Regulation of gene expression includes the processes that cells and viruses use to regulate the way that the information in genes is turned into gene products...
. When applied to myoblasts, myostatin inhibits their differentiation
Differentiation
Differentiation may refer to:* Differentiation , the process of finding a derivative* Differentiated instruction in education* Cellular differentiation in biology* Planetary differentiation in planetary science...
into mature muscle fibers.
Recently, myostatin has also been shown to inhibit Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
, a kinase that is sufficient to cause muscle hypertrophy
Muscle hypertrophy
Muscle hypertrophy is an increase in the size of muscle cells. It differs from muscle hyperplasia, which is the formation of new muscle cells.-Hypertrophy stimuli:A range of stimuli can increase the volume of muscle cells...
, in part through the activation of protein synthesis
Protein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...
.
Therefore, myostatin acts in two ways, by inhibiting muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
and by inhibiting Akt-induced protein synthesis.
Clinical significance
Further research into myostatin and the myostatin gene may lead to therapies for muscular dystrophyMuscular dystrophy
Muscular dystrophy is a group of muscle diseases that weaken the musculoskeletal system and hamper locomotion. Muscular dystrophies are characterized by progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue.In the 1860s, descriptions of boys who...
. The idea is to introduce substances that block myostatin. In 2002, researchers at the University of Pennsylvania
University of Pennsylvania
The University of Pennsylvania is a private, Ivy League university located in Philadelphia, Pennsylvania, United States. Penn is the fourth-oldest institution of higher education in the United States,Penn is the fourth-oldest using the founding dates claimed by each institution...
showed that monoclonal antibody specific to myostatin improves the condition of mice with muscular dystrophy, it is presumed, by blocking myostatin's action. Similar results in monkeys were published in 2009.
In 2005, Lee showed that a two-week treatment of normal mice with soluble activin type IIB receptor, a molecule that is normally attached to cells and binds to myostatin, leads to a significantly increased muscle mass (up to 60%). It is thought that binding of myostatin to the soluble activin receptor prevents it from interacting with the cell-bound receptors.
It remains unclear as to whether long-term treatment of muscular dystrophy with myostatin inhibitors is beneficial: The depletion of muscle stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s could worsen the disease later on.
, no myostatin-inhibiting drugs for humans are on the market, but an antibody genetically engineered to neutralize myostatin was developed by New Jersey pharmaceutical company Wyeth
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
. The inhibitor is called MYO-029, but, after an initial clinical trial, Wyeth says they will not be developing the drug. Some athletes, eager to get their hands on such drugs, turn to the internet, where fake "myostatin blockers" are being sold.
Myostatin levels are effectively decreased by creatine
Creatine
Creatine is a nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of Adenosine triphosphate...
supplementation.
A technique for detecting mutations in myostatin variants has been developed.
In fiction
A fictional drug called myostatin is featured in the TV series The Incredible Hulk episode "A Death in the Family" (Season 1, Episode 2). This episode came out about 20 years before real myostatin was discovered.In the Japanese manga
Manga
Manga is the Japanese word for "comics" and consists of comics and print cartoons . In the West, the term "manga" has been appropriated to refer specifically to comics created in Japan, or by Japanese authors, in the Japanese language and conforming to the style developed in Japan in the late 19th...
Air Gear
Air Gear
is a shōnen manga written and illustrated by Ito "Oh Great" Ōgure. Air Gear revolves around the life of Itsuki Minami "Ikki", also known as "Baby Face", "Lil Crow", and his friends. The story follows their use of Air Treks, an in-universe invention derived from inline skates...
, the two characters Akira Udou and Mitsuru Bandou have this condition.