Myogenesis

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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

Myogenesis

Stage	Associated genetic factors
Delamination	Pax3; c-met
Migration	c-met/HGF; Lbx1
Proliferation	? Pax3; c-met; Mox2; Msx1; Six; (Myf5; MyoD)
Determination	Myf5; MyoD
Differentiation	Myogenin; Mcf2; Six; (MyoD; Myf6)
Specific muscle formation	Lbx1; Mox2
Satellite cells	Pax7

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

Mesodermal cells
- 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
      - 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

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

Head & Neck musculature⁶

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
- 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

Muscle Growth

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

Muscle Regeneration⁵

Pluripotent stem cell

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
- 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 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

Intrinsic programs in muscle precursor cells

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
    - 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
  - 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
  - MyoD
    - 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
- 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

Secreted factors regulating embryonic muscle development

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

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References
1. Neuromuscular Disorders 2002;12:438�446
2. Gene Therapy 2002;9:642�647; J Cell Biology 2002;157:851�864
3. Nature 2002;420:418-421; BBRC 2003;300:965-971
4. J Anat 2003;202:59�68, EMBO reports 2003;4:855-860
5. Nature Rev Genet 2003;4:495-505
6. Trends Genet 2007 May 22

10/30/2007

MYOGENESIS & MUSCLE REGENERATION

Stages in Muscle Development4

General mechanisms underlying muscle development1

Stages in Muscle Development⁴

General mechanisms underlying muscle development¹