Skeletal Muscle Development

8/9/2019 Skeletal Muscle Development

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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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Skeletal Muscle Development