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General mechanisms
  Early myogenesis:
    Intrinsic programs
  Secreted factors
  Other molecules
Muscle development
  Head & Neck
    Stem cells
    Myogenic progenitors
    Satellite cells
    Side population cells
Membrane repair
Muscle growth
bHLH transcription factors
Bone morphogenetic proteins (Bmp)
Fibroblast growth factors
MEF2 family
Mnf (FOXK1)
Myogenic determination factors
Myogenin (Myf4)
Myomaker (TMEM8C)
Pax3 associated (Eya; SIX)
Sonic hedgehog (SHH)

From: A Kornberg

Stages in Muscle Development 4


Stage Associated genetic factors Mutant effects
Delamination Pax3; c-met Pax3 mutant: No c-met expression; No lateral migration
Migration c-met/HGF; Lbx1 Migration does not occur
Proliferation ? Pax3; c-met; Mox2; Msx1; Six; (Myf5; MyoD) No proliferation
Determination Myf5; MyoD Myf5 + MyoD muations: Myogenic cell adopts non-muscle phenotype
Differentiation Myogenin; Mcf2; Six; (MyoD; Myf6) Mutants remain as myocytes
Specific muscle
Lbx1; Mox2 Lbx1 mutants: Extensor & Hindlimb muscle
Mox-2 mutants: Forelimb & Hindlimb muscle
Satellite cells Pax7 Satellite cells absent; No postnatal muscle growth
Head & Neck musculature 6
Muscle Growth
Membrane Repair Pathways 10
Muscle Regeneration 5
  • 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
    • 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 cells: General 11
    • Tissue specific stem cell in mammalian limb skeletal muscle
    • Location: Periphery of muscle fibers; Close to plasma membrane
    • Developmental origin: Dermomyotome
    • Molecular label: Pax7
    • Limb muscles
      • Satellite cells quiescent
      • Activated by exercise or damage
    • General actions
      • Muscle growth: Fuse to muscle fibers longitudinally & radially
      • Contribute new muscle nuclei
      • Craniofacial & Extraocular muscles
        • Satellite cells, less quiescent: Actively contribute to homeostasis
  • Satellite cell: Quiescent
    • 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 & Regeneration of muscle
    • Other features
      • Multipotent
        • May differentiate into: Muscle, Bone, Fibroblast or Fat
        • Aged satellite cells: More likely to differentiate outside myogenic lineage
      • Cell division may be asymmetric
        • May generate daughter cells for renewal or differentiation
        • Associated with Numb protein
      • Limited capacity for replication
      • SC in Aging muscle
        • SC numbers
          • Variably maintained or reduced
          • More loss: Females
          • Less loss: Exercise
        • SC properties
          • Formation of myogenic colonies: Reduced
          • Ability to activate & proliferate: Decreased
          • Capacity to differentiate & fuse into myotubes: Impaired
          • Apoptosis: More likely
          • Increased propensity to exit quiescent state
          • FGF2 signal: Increased
    • Molecules expressed
      • Pax7
        • PAX7 protein
          • 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
        • Animal model: Pax7 mutations
          • Satellite cells: Absent
          • Embryonic muscle development: Normal
          • Postnatal muscle growth: None
          • Pluripotent stem cells still present
          • Disrupt function of embryonic, but not adult, stem cells
        • PAX7 disorders
      • 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
        • Actions
          • Down-regulates expression of MyoD & other muscle regulatory factors
          • May interact with Pax3
          • Promotes muscle cell de-differentiation & proliferation
          • Ensure correct expansion of myogenic precursors before arrest & 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)
    • Stimuli to activation: Muscle
      • Injury
      • Stretch
      • Mechanical load
    • Molecular markers
    • Development
      • Arise during late stages of embryogenesis
      • Highly active during postnatal growth of muscle tissue
      • Provide most of myonuclei to adult muscles
    • Regeneration: Stages
      • Satellite cells
        • Necessary for adult muscle regeneration
        • Not necessary for recovery of size after disuse
      • Activation: Associated with MyoD
      • Proliferation
        • Related to Myf-5
        • Midkine: Expressed by small regenerating muscle fibers
      • Fusion
    • Muscle usage 7
      • Muscle fiber hypertrophy
        • Normally occurs with fusion of satellite cells with muscle fibers
        • May occur without satellite cells: Increase of
          • Myonuclear domain size
          • Myonuclear size
        • Increase in muscle fiber size from myostatin inhibition or Akt overexpression
          • May occur without satellite cellproliferation
      • Addition of new small muscle fibers
        • Requires satellite cells
        • Fibers have immature myosin patterns
    • Differentiated product: Myoblast
  • Myokines
  • 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
  • Myogenesis: Satellite cell vs Embryonic
    • Regeneration more dependent than embryogenesis on MyoD
    • Pax7 required for ontogeny of satellite cells but not embryonic precursors
  • Regenerating muscle fibers (After necrosis)(Arrow): Pathology
    • Small
    • Large nuclei
    • NADH: Dark staining
    • May occur individually or in clusters

    NADH stain

PAX 7 stain
Satellite cells in Duchenne MD

Muscle Regeneration: Pathways

General mechanisms underlying muscle development 1

Intrinsic programs in muscle precursor cells Secreted factors regulating embryonic muscle development
Return to Neuromuscular Home Page

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