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SKELETAL MUSCLEDEVELOPMENT
Januar M. Aujero
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THREE TYPES OF MUSCLESkeletal, cardiac, and smooth muscle differ in:
Microscopic anatomy
Location
Regulation by the endocrine system
and the nervous system
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FUNCTION
SMotion: external (walking, running, talking,
looking) and internal (heartbeat, blood pressure,digestion, elimination) body part movements
Posture: maintain body posture
Stabilization: stabilize joints muscles have
tone even at rest
Thermogenesis: generating heat by normalcontractions and by shivering
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SKELETAL MYOGENESIS
Myology: the scientific study of muscle
muscle fibers = muscle cells
myo, mys & sarco: word roots referring to
muscle
Myogenesis- Formation of muscular tissue , in particular
during embryonic development
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Intermediate mesoderm
Chordamesoderm
Paraxial mesoderm somitic dorsal mesoderm
Lateral mesoderm
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SKELETAL MYOGENESIS
Skeletal muscle is
mesodermal in origin.
Somites
yDermatome
ySclerotome
yMyotome
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Sclerotome
Mesenchymal cells
Location: Ventral somite
Derivatives: Ribs & Vertebrae
DermomyotomeEpithelial structure
Forms from somites
Location:Dorsal somite
Derivatives: Skin & Skeletal muscles
Epaxial: Back muscles
Hypaxial: Trunk & Limb muscles
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Myotome
Origin: Dermomyotome
Derivative: Trunk muscle
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SKELETAL
MYOGENESIS
Begins soon after onset of
somitogenesis and continues
throughout development andpostnatal growth.
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Somites give rise to the
cells that form the vertebrae
and ribs, the dermis of the
dorsal skin, the skeletal
muscles of the back, and
the skeletal muscles of the
body walls and limbs.
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DETERMINING SOMITIC CELL FATES Determination of the sclerotome and the dermatome
Determination of the myotome
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How is an embryonic mesenchymal cell
instructed to form a muscle tissue instead
of a cartilage cell, a fibroblast, or an
adipose cell?
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In 1986, Lassar
and co-workers
took DNA from
myoblast cellsand transfected
it into embryonic
mouse cell type,
the C3H101-2
cell.
When the muscle
DNA was added to
these cells, the
C3H101-2 cells weretransformed into
muscle cells.
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While DNA isolated from fibroblasts or
other cell types cannot accomplish this
conversion.
WHY?
-due to absence in them of a myoblast-
specificmRNA
MyoD a protein encoded by the myoblast
mRNA
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MyoDgene expressed only in cells
of the muscle lineages
- master switch , it can
convert other cell types
into muscles if this gene is
active in them.
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The hypothesis was
tested by cloning
myoD gene into a
viral vector.
-when this myoD gene wastransfected into various
cell types, pigment cells,
nerve cells, fibroblasts,
and liver cells they wereconverted into muscle-like
cells.
*Thus, myoD appears to activate the
muscle-specific genes that make up the
muscle phenotype.
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MyoDis not the only muscle switch gene.
MyoDfamily or myogenic bHLH proteins
1. Myogenin
2. Myf5
3. MRF4
Transfection of any of these
myogenic genes into a wide range
of cultured cells also converts these
cells into muscles.
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In some instances, these myogenic
transcription factors can compensate for the
loss of one or the other.
In 1992, Rudnicki and colleagues showed that
Myf5 and MyoD can accomplish the same
functions.
When mice lack myoD genes, the expression of the myf5 genetakes over. The resulting mice have normal muscle
development.
When the nice lack their myf5 genes , they also have normal
muscle development.
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Muscle commitment and differentiation mediated by the MyoD family of transcription factors.
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How are the MyoD
proteins turned on?
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George-Weinstein and her colleagues(1996)
have demonstrated that when chickepiblasts are isolated from the rest of
the gastrula and separated into their
individual cells, these epiblast cells
become muscle.
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It appears that the epiblast cells have the
preferred ability to become committed to
myoblasts, and it is only their interactions
with other cell types that prevent their
becoming muscles
growth factors:
FGF, myostatin, Growth factor receptor-bound protein 2,
Calcineurin, MEF2 family,TGF, Laminins
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Twist protein a DNA-binding protein thatlooks very much like MyoD
-inhibit MyoDand other such
proteins from binding to the
promoters of their target
muscle-specific genes
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MEF2A induces fibroblasts to become muscles,
and it appears to coperate with MyoD on the
enhancers of muscle-specific genes.
Kaushal and colleagues (1994) speculate that MEF2A
provides additional specificity to MyoD binding such
that MyoD doesnt inadvertantly activate non-muscle
genes that have a regulating sequence capable ofbinding bHLH proteins.
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GOVERNING THE SWITCH BETWEEN MUSCLE
CELLPROLIFERATION AND DIFFERENTIATION
y Muscle cells do not generally become
differentiated until after they have finished
proliferating.
y Proliferating muscle cells do not express the
muscle-specific phenotype, while differentiated
muscles no longer divide.
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MYOTUBE FORMATION
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MUSCLE CONVERSION
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MUSCLE GROWTH
Primarymusclefibers
y
First fibers that form in muscley Form from primarymyoblasts
yTend to become slow muscle
fibers
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Secondarymusclefibers
y Form around primary fibers
y Generated near time ofinnervation
y Form from secondary myoblasts
y
Tend to acquire features of fastmuscle fibers
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Latermusclefibers
y
Progenitors: Satellite cells
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Stage Associated genetic factors Mutant effectsDelamination 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-musclephenotype
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
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HOMEOSTATIC IMBALANCES
The muscular dystrophies (MD) are a group of morethan 30 genetic diseases characterized byprogressive weakness and degeneration of theskeletal muscles that control movement.
Some forms ofMD are seen in infancy or childhood,while others may not appear until middle age orlater.
The disorders differ in terms of
y the distribution and extent of muscle weaknessy (some forms ofMD also affect cardiac muscle)
y age of onset
y rate of progression
y pattern of inheritance
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HOMEOSTATIC IMBALANCES
Duchenne Muscular Dystrophy:
Inherited lack of functional genefor formation of a protein,
dystrophin, that helps maintainthe integrity of the sarcolemma
Onset in early childhood, victimsrarely live to adulthood
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