Myostatin Lecture Notes

Myostatin (Mstn) is an autocrine, paracrine, and endocrine factor that regulates muscle mass.

Kinase: An enzyme that transfers a phosphate (PO4) group from one molecule to another; common in second messenger signaling.
TGFβ (Transforming Growth Factor Beta): A family of growth factors, including myostatin.
Mstn: Abbreviation for myostatin.
GDF (Growth and Differentiation Factor): A subclass of TGFβ; myostatin is GDF8 in vertebrates.
BMP (Bone Morphogenic Protein): Another subclass of TGFβ.
Activins: Another subclass of TGFβ.
ActRII: Activin type II receptor; a transmembrane receptor that binds activin and myostatin.
ALK (Activin-like Kinases): Family of kinases that bind to ActRII, forming an enzyme-linked receptor; phosphorylates Smad proteins.
Smads: Transcription factors involved in myostatin signaling. R-Smad is activated by myostatin, Co-Smad binds R-Smad, and I-Smad inhibits R-Smad.
Transcription Factor: Proteins that bind to DNA and regulate gene expression.
Akt: Protein kinase that promotes growth by activating pathways for protein synthesis.
Follistatin: Antagonizes activins and myostatin, acting as an autocrine, paracrine, and endocrine factor.
IGF (Insulin-like Growth Factor): Antagonizes myostatin action.
GASP: Antagonizes myostatin.

Mstn Mutations: Discovered by knocking out GDF8 in mice, leading to larger muscles.
Double Muscle Cattle: Intentional breeding of cattle with natural myostatin mutations leads to increased muscle mass; specific mutations identified.
Human Cases: A human with non-functional myostatin showed prominent muscle development in infancy but had decreased muscle force generation.

Peptide Hormone: Limits muscle size.
Regulation of Expression
- Decreased by signals indicating muscle size is appropriate.
- Increased by signals indicating muscle use is limited or muscle breakdown is needed.
Functioning Pathway: Conventional protein secretory pathway; myostatin is produced in the rough endoplasmic reticulum (RER), dimerized, and secreted as an inactive complex.

Binding and Activation: Myostatin binds to the ActRIIB/ALK receptor complex on muscle cells.
Phosphorylation of Smads: R-Smad2 and R-Smad3 phosphorylated, forming a complex with Co-Smad4 which translocates to the nucleus to regulate gene expression.

Inhibition of Protein Synthesis: This is achieved by inhibiting Akt, which promotes protein synthesis.
Blocking Cell Differentiation: Inhibits satellite cell differentiation, preventing muscle repair and growth.
Initiation of Protein Degradation: Triggers protein breakdown pathways, leading to muscle wasting.

ActRIIB Receptor Mutations: Prevent myostatin activation.
Increased Follistatin Expression: Blocks myostatin action even if normal myostatin and receptor are present.
IGF Activity: IGF activates Akt, counteracting the actions of myostatin.

Evolution of Myostatin: Myostatin (GDF8) evolved from a growth factor present in invertebrates and lower vertebrates; GDF11 has broader functions in invertebrates.