Home, Search, Index, Links, Pathology, Molecules, Syndromes, Muscle, NMJ, Nerve, Spinal, Ataxia, Antibody & Biopsy, Patient Info

MYOGENESIS & MUSCLE REGENERATION

General mechanisms   Early myogenesis:     Intrinsic programs   Secreted factors   Other molecules Muscle development   Head & Neck   Myogenesis     Stem cells     Myogenic progenitors     Satellite cells     Side population cells     Myoblasts     Myotubes   Regeneration

bHLH transcription factors Bone morphogenetic proteins (Bmp) Calcineurin c-met Desmin Fibroblast growth factors Follistatin GRB2 Laminins Lbx1 M-cadherin MEF2 family Midkine Mnf (FOXK1) Mox2 Msx1 Myf5 Myf-6 MyoD Myogenic determination factors Myogenin (Myf4) Myostatin Noggin Pax3 Pax3 associated (Eya; SIX) Pax7 Sonic hedgehog (SHH) TBX1 TGFβ VCAM1

From: A Kornberg

Stages in Muscle Development⁴

• Mesodermal cells
  

  Dorsal Ventral Sclerotome   Mesenchymal cells   Location: Ventral somite   Derivatives: Ribs & Vertebrae Dermomyotome   Epithelial structure   Forms from somites   Location: Dorsal somite   Derivatives: Skin & Skeletal muscles     Epaxial: Back muscles     Hypaxial: Trunk & Limb muscles Myotome   Origin: Dermomyotome   Derivative: Trunk muscle DRG: Dorsal root ganglion

  • Location: Paraxial
  • Cells not committed to specific muscle lineage
• Myogenic progenitors
  • Definition of cell type
    • Normal developmental fate is muscle
    • Not terminally differentiated
  • Location: Cephalic mesenchyme & Prechordal plate
    • Precursors for: Head muscles
  • Location: Somites
    • Epaxial lineage
      • Origin: Dorsomedial somites
      • Precursor for: Back (Dorsal) muscles
    • Hypaxial lineage
      • Origin: Dorsolateral somites
      • Precursor for
        • Body wall ventral muscles
          • Via extension of myotome
        • Appendicular & Tongue muscles
          • Via migration of precursor cells
      • Formation regulated by
        • Lateral-plate mesoderm
        • Signals inhibit myogenesis
        • Bmp-2, Bmp-4 & Bmp-7
          • Can replace inhibitory activity of lateral-plate mesoderm
          • Prevents premature activation of MyoD
        • Dorsal ectoderm
          • Provides signals that stimulate myogenesis & activate expression of MyoD
          • Signals from dorsal ectoderm can be mimicked by Wnt-4, Wnt-6 & Wnt-7a
            • Wnt-7a activates expression of MyoD: Leads to co-expression of MyoD and Myf5
            • Soluble Frizzled-related proteins (sFRPs) block Wnt signalling: Inhibit myogenesis
  • Migration
    • Components: Delamination & Movement into limb
    • Positional cues for progenitor cells: Mesenchymal cells of limb
    • Dependent on: c-met
  • Genes expressed during early myogenesis in migrating precursor cells
    • Pax3
    • Mox-2
    • Lady Bird homolog (LBX1) :
    • Basic helix-loop-helix transcription factors
      • Molecules
        • Myogenin (Myf-4)
        • Myf-5
        • Myf-6
        • MyoD
      • Expression: When progenitor cells reach limb
    • Mnf (FOXK1)
    • Msx1
  • Secreted factors regulating embryonic muscle development
    • Sonic hedgehog (SHH)
    • Bone morphogenetic protein (Bmp) family
    • Noggin
    • Follistatin
• Myoblasts
  • Developmental features
    • Proliferating cells
    • Fully determined to myogenic phenotype
    • Capable of terminal differentiation
  • Subtypes
    • Embryonic
      • Derived from somites
      • Oligoclonal founders form muscle fibers
    • Fetal: May have endothelial origin
    • Adult (Satellite cells)
  • Molecular features: Usually express myogenic determination factor genes
    • MyoD
    • Myf-5
    • Myogenin (Myf-4)
    • Mrf4 (Myf-6, Herculin)
  • Other molecules in late myogenesis (after specification)
    • Fibroblast growth factors
    • Myostatin
    • Growth factor receptor-bound protein 2 (GRB2) molecules
      • Growth factor receptor-bound protein 2 (GRB2)
      • Hepatocyte growth factor (HGF)
      • c-met: HGF receptor
    • Calcineurin pathway
      • Calcineurin
      • Nuclear factor of activated T-cells calcium responsive isoform 3 (NFATC3)
    • MEF2 family
    • TGFβ
    • Laminins
• Myotubes
  • Terminally differentiated muscle cell
  • Multinuclear
  • Two waves of formation
    • Primary myotubes: Earlier migration; Provide scaffold
    • Secondary myotubes: Later migration
  • Grow & elongate by cell fusion
• Muscle fibers
  • Mature myotubes
    • Exhibit cross-striated myofibrils
    • Surrounded by basal lamina

• Features distinct from somite-derived muscles
  • Muscle derivation: Branchiomeric & other
  • Innervated by Phox2b-dependent visceral motor neurons
  • May express myosin isoforms not found in other skeletal muscles (Masseter)
• Branchiomeric muscle derivation: Muscles derived from progenitor cells in branchial arches
  • General
  • Origination: Cranial mesoderm (Paraxial & Anterior occipital)
    • Neighboring cells in cranial mesoderm are cardiac progenitors
  • Migration: Lateral
  • Mastication: Jaw opening & closing
    • Origination: 1st branchial (Mandibular arch)
    • Muscles: Temporalis; Masseter; Digastric
    • Absent masticatory muscles
      • Mouse model: Knockout of both Tcf21 & Msc
  • Facial expression
    • Origination: 2nd branchial (Hyoid arch)
    • Muscles: Orbicularis oris & oculi; Frontalis; Mentalis
  • Pharyngeal function
    • Origin: 3rd branchial
• Non-branchiomeric muscle derivation
  • Extra-ocular muscles: Derived from anterior-most paraxial & pre-chordal mesoderm
  • Tongue muscles: Hypoglossal cord; Anterior somites
  • Ventral neck muscles: Somites
• Molecular associations
  • Upstream regulators of branchiomeric myogenesis
    • TBX1
      • T-box containing transcription factor
      • Required for: Myogenic regulatory factor (MRF) gene activation during branchiomeric myogenesis
      • Regulates
        • Onset of branchiomeric myogenesis
        • Transcriptional activation of myogenic determination genes (Myf5 & MyoD) in the mandibular arch
      • Deletion
        • Failure of caudal pharyngeal morphogenesis
        • Craniofacial & cardiovascular defects
        • Reduced expression in pharyngeal mesoderm
          • Myogenic factors: Myf5 & MyoD
          • Tlx1 & Fgf10
        • No effects on cell migration factors: Capsulin; MyoR
    • Cell migration factors
      • Tcf21 (Capsulin)
      • Msc (MyoR; Musculin)
    • Pitx2
      • Homeobox-containing transcription factor
      • Controls core mesoderm survival & Myf5 activation
      • Acts through Msc to control cell proliferation & survival in 1st arch
      • Expressed in somites after initial myogenic differentiation
    • Cardiac muscle cells have similar pattern of regulatory molecules
  • Myf5
    • Earliest expressed myogenic regulatory factor gene
    • Activation regulated by separate cis-acting elements from trunk musculature
  • Fibroblast growth factor 8 (FGF-8): Promotes branchiomeric versus eye muscle fate in 1st arch
  • Negative signaling molecules
    • Bone morphogenetic proteins (BMP): BMP4 & BMP7
    • Wnt proteins
    • Arise from pharyngeal epithelium
  • No expression or prominent role in developing head muscles
    • Pax3
    • Mrf4
• Disease associations
  • del22q11.2 Syndromes
    • DiGeorge Syndrome
    • Velo-Cardio-Facial Syndrome

• Primary muscle fibers
  • First fibers that form in muscle
  • Form from primary myoblasts
  • Tend to become slow muscle fibers
• Secondary muscle fibers
  • Form around primary fibers
  • Generated near time of innervation
  • Form from secondary myoblasts
  • Tend to acquire features of fast muscle fibers
• Later muscle fibers
  • Progenitors: Satellite cells

• Pluripotent stem cell
²
• Functions
  • Self-renewal: Capable of high proliferation
  • Multipotential: May differentiate into different lineages
    • Muscle, Neural, Bone, Fat, Hematopoietic or Cartilage
• Location: Beneath basal lamina of normal myofibers
• Molecular markers
  • Sca-1
  • Bcl-2
  • CD34: +/-
  • Negative for all myogenic regulatory factors (MRFs), MHC1 & Pax7
• Functional characteristics
  • Commonly remain quiescent
  • Bmp-2: Stimulates conversion to bone pathway
  • Transplantation: More effective at restoring dystrophin than satellite cells
  • Immunogenicity: Relatively low
  • May provide muscle fiber precursors during regeneration
• Satellite cell: Quiescent

PAX 7 stain Satellite cells in Duchenne MD

• Definition
  • Quiescent myoblast
  • Location: Adjacent to muscle fiber sarcolemma; Beneath basal lamina
  • Embryonic origin unclear
    • Contain endothelial cell markers
    • May originate from somite or cells associated with embryonic vasculature
  • Adult origins
    • Other satellite cells
    • Bone marrow cells
    • SP cells
• Function: Repair and regeneration of healthy muscle
• Other features
  • Multipotent: May differentiate into muscle, bone or fat
  • Cell division may be asymmetric
    • May generate daughter cells for renewal or differentiation
    • Associated with Numb protein
  • Limited capacity for replication
  • Numbers maintained in old muscle
• Molecules expressed
  • Pax7
    • Subcellular location: Nuclear
    • Can bind as heterodimer to Pax3
    • Commits pluripotent stem cells to myogenic lineage
    • May function in specification of satellite cells upstream of MRFs
    • Pax7 mutations
      • Satellite cells: Absent
      • Embryonic muscle development: Normal
      • Postnatal muscle growth: None
      • Pluripotent stem cells still present
  • Heparan sulfate proteoglycans
    • Syndecan-3
    • Syndecan-4
  • Mnf: Responsible for timing of expression of genes for
    • Myogenic determination
    • Cell cycle progression
  • Muscle segment homeobox 1 (Msx-1; HOX7)
    • Subcellular location: Nuclear
    • Homeobox transcription factor
    • Expression
      • Lateral domain of dermomyotome
      • Migrating forelimb muscle progenitor cells
    • Actions
      • Down-regulates expression of MyoD & other muscle regulatory factors
      • May interact with Pax3
      • Promotes muscle cell de-differentiation & proliferation
      • May ensure appropriate expansion of myogenic precursors before arrest and differentiation
    • Mutations: Hypodontia; Witkop syndrome
  • ± MyoD
    • Promotes regenerative ability
    • Upregulated in dystrophin deficient & inflammatory myopathies
    • Mice deficient in dystrophin & MyoD: Severe phenotype
  • CD34 (Hematopoietic progenitor cell antigen) : Truncated form
  • V-CAM1
  • c-met (Hepatocyte growth factor receptor)
  • Pax3
    • Present in satellite cells in some proximal muscles
    • Absent from limb muscle satellite cells
  • NCAM (CD56)
  • No myogenic regulatory factors
• Sub-populations
  • EP: Proliferate well
  • LP: Slow division; Lack of fusion; 1% of satellite cells
• Satellite cell: Activated (Proliferating myogenic precursor)

  Muscle Regeneration: Pathways

  • Molecular markers
    • M-cadherin
    • Pax-7
    • c-Met (Hepatocyte growth factor receptor)
    • CD34 (Hematopoietic progenitor cell antigen) : Full length
    • Myogenic regulatory factors
      • Myf5
      • MyoD
      • Myogenin: Some cells
    • Desmin
  • Development
    • Arise during late stages of embryogenesis
    • Highly active during postnatal growth of muscle tissue
    • Provide most of myonuclei to adult muscles
  • Regeneration: Stages
    • Activation: Associated with MyoD
    • Proliferation
      • Related to Myf-5
      • Midkine: Expressed by small regenerating muscle fibers
    • Fusion
  • Differentiated product: Myoblast
• Side population (SP) cells
  • Cells with heterogeneous hematopoetic & myogenic capacities
  • CD45 positive subpopulation can develop myogenic specificity: May express Pax7
  • Injured muscle: SP cells
    • Stimulated by Wnt (Wingless) pathway
    • May replenish satellite cell population during muscle regeneration
• Terminal differentiation
  • Molecular markers
    • Myogenin
    • Myf-6 (MRF-4)
• Myogenesis: Satellite cell vs Embryonic
  • Regeneration more dependent than embryogenesis on MyoD
  • Pax7 required for ontogeny of satellite cells but not embryonic precursors

General mechanisms underlying muscle development¹

• Genes expressed during early myogenesis in migrating precursor cells
  • Pax3
    • Pax molecule family structure: Contain homeobox & paired box
    • Subcellular location: Nucleus
    • Pax Function & Actions: Role in myogenic specification
      • Stimulates proliferation of precursors in different lineages
      • Induces activation of MyoD expression
      • Interacts with Msx1
      • Required for: Delamination of myogenic precursors from hypaxial dermomyotome
      • Mechanism: Mediates transcription of c-met gene
    • Expression
      • Highest during embryonic stages; Reduced during fetal life
      • Expressed in myotome precursor (dermomyotome) cells
      • Occurs in all migrating hypaxial cells
      • Not present during facial muscle development
    • Pax3 positive cells do not express myogenic regulatory factors (Mrf)
    • Pax3 associated molecules: Homeobox genes
      • Regulate proliferation of muscle premasses in somites
      • Drosophila 'dachshund' gene
      • Eya 2
      • Eya 4
      • 'sine oculis' (SIX 1) : Regulates embryonic myogenesis
      • SIX 4
    • Pax3 mutations
      • Waardenburg syndrome I
      • Waardenburg syndrome III
      • Craniofacial-Deafness-Hand syndrome (CDHS)
      • Rhabdomyosarcoma-2
        • Chromosomal translocation T(2;13)(Q35;Q14) involving PAX-3 & FOXO1A
        • Constitutionally active Pax3
      • Mouse knockout
        • Absent limb muscle: No embryonic muscle formation
        • Preserved head muscles
      • Splotch mice: Pax3-deficient
        • Defective lateral migration & reduced proliferation in dermomyotome
        • Limb & diaphragm muscles are not formed
  • Mox-2 (MEOX-2)
    • Homeobox containing transcription factor
    • Role in mesoderm induction & regional specification
    • Deletion
      • Myogenic precursor proliferation in limb impaired
      • Limb muscle patterning abnormal
        • Forelimbs: Certain muscles totally missing
        • Hindlimb muscles: Reduction in size
  • Basic helix-loop-helix (bHLH) transcription factors
    • General
      • Subcellular localization: Nuclear
      • Bind DNA: Requires dimerization with second bHLH protein
      • bHLH domain
        • Required for DNA binding & dimerization with E-protein family of transcription factors
        • MRF–E protein heterodimers & MRF monomers
          • Bind to consensus E-box sequence CANNTG: Found in promoters of many muscle-specific genes
      • C-terminal amphipathic α-helix has discrete functions
        • MyoD
          • Specification domain
          • Initiates transcription from normally silent genes
        • Myogenin
          • General transactivation domain
          • Amplifies level of expression of genes that are already being expressed (with open chromatin structure)
      • General actions: Induce fibroblasts to differentiate into myoblasts
      • Myf-5 or MyoD is needed for determination & proliferation of skeletal myoblasts
      • Upregulated in regenerating muscle fibers
      • Pax3 & Pax7 act upstream of bHLH factors
      • bHLH Proteins
        • Myogenic regulatory factors (MRFs)
          • Upstream: MyoD; Myf-5
          • Downstream: Myogenin; Myf-6
        • Other: Twist; ITF-2
    • Myogenin (Myf-4)
      • Associated with terminal differentiation & fusion of myogenic precursor cells to new or existing fibers
      • Mouse knockout
        • Skeletal muscle mass: Loss, especially latero-ventral body wall
        • Differentiated muscle fibers: Loss, severe
        • Undifferentiated myoblasts: Normal
      • Rhabdomyosarcomas: Overexpression
    • Myf-5
      • Expression
        • Positively regulated by: Sonic hedgehog; Wnt1; MyoD
      • Function: Myoblast proliferation
      • Inactivation in mice
        • Delayed development
          • Myotome
          • Paraspinal, deep back & intercostal muscles
        • Normal limbs
      • Combined MyoD and Myf5 knockout: Complete absence of skeletal muscle
    • Myf-6 (MRF4; Herculin)
      • Skeletal muscle specific
      • May be involved in differentiation of myotubes
        • Associated with terminal differentiation & fusion of myogenic precursor cells to new or existing fibres
      • Mutation may
        • Produce mild centronuclear myopathy
        • Exacerbate Becker muscular dystrophy
    • MyoD1 (MYF3)
      • Forms heterodimers with ITF-2 (bHLH protein)
      • Inhibited by Twist protein (bHLH protein)
      • Target gene
        • Transcription factor Slug (Snai2)
      • Function
        • Induction of cell-cycle arrest & differentiation
      • Inactivation in mice
        • Delayed muscle development in limbs
        • Increased numbers of satellite cells
        • Deficient regenerative processes
      • Overlap: Inactivation of both MyoD & Myf-5 causes complete absence of myoblasts
  • Lady Bird homolog (LBX1)
    • Homeobox
    • Subcellular localization: ? Nuclear
    • Function in myogenesis
      • Acquisition of muscles in dorsal forelimb
      • Associated with movement of dorsal muscle masses into limb after delamination
    • Deletion: Loss of limb muscles
      • Hindlimb muscles: Very severely affected
      • Forelimb muscles: Cells migrate to ventral muscle mass; Flexor, but not extensor, muscles form
  • Mnf (FOXK1)
    • Transcriptional activator
    • Subcellular location: Nuclear.
    • Binds to the upstream enhancer region (CCAC box) of myoglobin gene
    • Roles
      • Myogenic differentiation
      • Remodeling of adult muscles in response to physiological stimuli
    • Inactivation in mice: Reduced muscle mass & regeneration
  
  
• Other molecules in myogenesis
  • Myostatin (GDF-8)
    • Member of TGFβ superfamily
    • Structure: Homodimer
    • Action: Negative regulator of skeletal muscle growth
      • Inhibits satellite cell differentiation
      • Receptor: Activin type II receptor B
      • After myostatin binding to receptor: Complex binds to ALK-4/5
      • 2nd messenger: SMAD 2/3
    • Negative regulators
      • Myostatin pro-peptide: Bound to myostatin in serum
      • Growth and differentiation factor-associated serum protein 1 (GASP-1)
      • Follistatin
      • Follistatin-related gene (FLRG)
    • Human disease
      • Myostatin mutation: Muscle hypertrophy
      • High levels: HIV infection with muscle wasting
      • Low levels in muscle: Muscular dystrophy
    • Animal disease
      • Inactivation
        • Increase in muscle mass due to hyperplasia & hypertrophy
        • Double-muscled cows
      • Myostain blockade by antibody³
        • Increased muscle mass in normals
        • Improved strength in dystrophic muscle
      • Myostatin null
        • Muscle hypertrophy
        • Spindle excess
    • External links
      • GeneReviews
      • Wikipedia
  • Growth factor receptor-bound protein 2 (GRB2) pathway
    • Molecules
      • Growth factor receptor-bound protein 2 (GRB2)
        • Associates with activated tyrosine-phosphorylated EGF receptors & PDGF receptors
        • Regulates differentiation
      • Hepatocyte growth factor (HGF)
        • Mitogenic growth factor
        • Stages
          • Required for emigration of myoblasts from the somites into limb field
          • Role in secondary myogenesis
        • Requires heparan sulfate to transduce an intracellular signal
      • c-met (HGF receptor; MET)
        • Tyrosine kinase receptor
        • Ligand: Hepatocyte growth factor
        • Cell associations
          • Non-somitic mesodermal cells
          • Satellite cell marker
        • Associated myogenesis stages: Delamination; Migration; Proliferation
        • Mouse mutations
          • Impaired secondary myogenesis
          • No limb musculature
          • Precursor cells delamination & migration from somite: Normal
        • Disease: Papillary renal carcinoma
    • Functions
      • Sustain survival & proliferation of myoblasts during migration
      • Role in proliferation of myoblasts from which 2° myotubes are formed
  • Calcineurin pathway
    • Calcineurin
      • Found in all cells
      • Protein properties: Calcium-dependent, calmodulin stimulated protein phosphatase
      • Confers Ca⁺⁺ sensitivity
      • Action: Stimulates muscle hypertrophy
        • Stimulated by Ca⁺⁺
        • Stimulation causes association with GATA-2 transcription factor: Regulates gene expression
        • Associated with nuclear translocation of transcription factor NFATC1
      • Dominant-negative calcineurin mutant: Represses myocyte differentiation & hypertrophy
    • GATA-2: Increased expression in muscle
      • Activated by: IGF-1; Muscle regeneration
      • Effects: Muscle hypertrophy; Reduced age-related decrease in muscle mass
    • Nuclear factor of activated T-cells calcium responsive isoform 3 (NFATC3)
      • Downstream effector of calcineurin
      • Inactivation: Reduced muscle mass due to loss of primary myotubes
      • Calcineurin + NFATC3: Regulate expression of Myf5 in satellite cells
  • MEF2 family
    • Molecules
      • Myocyte-specific enhancer factor 2A
      • Myocyte-specific enhancer factor 2B
      • Myocyte-specific enhancer factor 2C
    • General functions
      • Induction & maintenance of muscle differentiation
      • Activation of muscle-specific gene expression: Developing cardiac, skeletal & smooth muscle
      • Functions with the peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α)
        • Directs slow-muscle-specific gene expression in adult muscle
        • PGC-1α
          • Upregulated during exercise
          • Targeted by calcineurin signaling to promote the specialization of adult muscle fibers
    • Expression levels
      • Present in many tissues
      • Upregulated: Development; Regeneration
      • Downregulated: After birth
    • Additive, or autoregulatory, action with bHLH (MRF) proteins
      • Expression of Myogenin & Mrf4 (Myf6) is dependent on both sets of transcription factors
  • TGFβ
    • Inactivates myogenic bHLH factors
    • Promotes fibrosis
    • Duchenne muscular dystrophy: TGFβ increased in muscle
  • Notch pathway
    • Temporal control of skeletal-muscle differentiation
    • Mechanisms
      • Regulation of MyoD expression
      • Negatively regulates muscle differentiation

• General: Environmental control signals influencing precursor cells
  • Location of signals: Ectoderm & Other
  • Ablation of ectoderm causes
    • Premature differentiation of muscle precursors in abnormal location
    • Underdevelopment of muscle
• Sonic hedgehog (SHH)
  • Member of TGFβ superfamily
  • Receptors: Patched ; Smoothened
  • Regulates muscle development
    • Stimulates expansion of muscle precursor population
    • Represses terminal differentiation of early myogenic precursor cells
    • Induces Pax3: Acts indirectly by inducing BMP proteins
    • Upregulates Myf-5: Binds to its receptor Patched (Ptc)
      • De-represses Smoothened (Smo)
      • Activates Gli family of transcription factors
      • Gli binds to specific sites in Myf5 promoter: Activates expression of Myf5 in epaxial somite
    • Functions
      • Function in hypaxial muscle: Spatially restricted to early myoblasts in ventral muscles of the posterior limb
      • Acts as permissive, not inductive, signal for slow MyHC expression in myoblasts
      • No function as a myoblast mitogen
  • Mouse knockout
    • Epaxial musculature: Absent
    • Hypaxial musculature: Reduced
  • Disorders
    • Mutations: Holoprosencephaly
    • ? Oncogene: Overexpression in Basal cell nevus syndrome
  • Also see: Desert hedgehog
  • External links
    • Hedgehog proteins
    • Hedgehog database
• Fibroblast growth factors: Actions
  • Regulate growth & differentiation of early embryonic primary myoblasts: FGF-1
  • ? Differentiation: Influences secondary & adult myoblasts
  • Require heparan sulfate to transduce an intracellular signal
• Bone morphogenetic protein (Bmp) family
• Noggin
  • Subcellular location: Secreted
  • Binds & inactivates TGFβ signalling proteins: Including Bmp4
  • Control
    • Induced by activin
    • Wnt signalling
  • Muscle
    • Restricts proliferative action of Bmp
    • Promotes differentiation
  • Mutations
    • Proximal Symphalangism
    • Tarsal-carpal coalition syndrome
    • Multiple-synostoses syndrome
    • Congenital stapes ankylosis syndrome
• Follistatin
  • Secreted glycoprotein
  • Binds to
    • Activin
    • Heparan sulfate proteoglycans
    • BMP7: ? Aids binding of Bmps to receptors
      • Stimulates muscle cell proliferation
      • Prevents Bmp-induced apoptosis
    • Myostatin
  • May modulate
    • Several members of TGFβ family
    • Myostatin: Inhibition in vivo
  • Overexpression in skeletal muscle: Increased muscle weight
  • Knockout: Muscle loss in diaphragm & intercostal muscles