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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
Membrane repair
Muscle growth
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
TMEM8C (Myomaker)
VCAM1

From: A Kornberg


Stages in Muscle Development 4

Myogenesis

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
  formation
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

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
7. Development 2011;138:3657-3666
8. Curr Opin Genet Dev 2015;32:162-170
9. Curr Opin Clin Nutr Metab Care 2018 Jan 30
10. Am J Physiol Cell Physiol 2020 Apr 29
11. FASEB J 2021;35(10):e21893

5/3/2020