20. Myogenesis: molecular basis of muscle development Flashcards
What is myogenesis?
The synthesis of new muscle
*Muscle cells are highly complex - full of metabolic & contractile proteins
How many muscle cells in a muscle fibre?
Muscle cells are huge when compared to most other cells. Each muscle fibre is a single muscle cell - up to 12cm long in humans!
What is the embryonic origin of muscle?
ZYGOTE > BLASTULA > GASTRULA > MESODERM > SOMITES > MYOTOME > MUSCLE
Myoblasts migrate out from the somite. What do medial and lateral somites give rise to?
Medial somite (near neural tube) - axial/trunk muscles Lateral somite (distal to neural tube) - limb muscles
All skeletal muscle from the neck down is derived from somites.
Embryonic origin of head and neck muscles
Some head and neck muscles are derived from the somite, such as the tongue.
Extra-ocular and jaw/facial muscles are not derived from somites (formed from head mesoderm).
Head muscles develop separately.
What is a syncytium?
a large mass of cytoplasm not separated into individual cells and contains many nuclei
ie. a muscle cell
How is a muscle fibre formed?
By fusion of a number of smaller precursor cells (myoblasts)
Myoblast vs. myotube vs. mature myofibres
MYOBLAST:
MPCs express genes to become even more specialised (myoblast)
-committed to become muscle but retain some characteristics of stem cells, eg. still highly proliferative
-spindle shaped
-centrally nucleated
MYOTUBE:
- terminally differentiated (no longer proliferative)
- central nuclear chain
MATURE MYOFIBRILS:
- nuclei move to periphery
- specialised structures develop (eg. t-tubules)
How is myogenesis regulated?
by complex network of:
- transcription factors
- growth factors
- microRNA (miRNA)
What transcription factors regulate myogenesis?
Muscle progenitor cells express specific patterns of transcription factors (characteristic: Pax3 & Pax7)
Embryos lacking both fail to develop muscle
Factors controlling expression of Pax3/Pax7 very complex:
-Sonic hedgehog (Shh), Wnts, Notch, noggin, BMP4
MRFs
Muscle progenitor cells begin to express myogenic regulatory factors (MRFs)
-need Pax3/Pax7
MRFs are very powerful transcription factors
-can even cause non-muscle tissue (fat, fibrotic tissue, liver) to try to become muscle
MRFs are all structurally similar
-basic helix-loop-helix (bHLH) family
MRFs to remember: MyoD, Myf5, Myogenin, MRF4
What are the primary MRFs?
MyoD & Myf5
INITIATE DIFFERENTIATION
They are expressed early in muscle development
Promote expression of Myogenin & beginning of differentiation
They are vital to myogenesis but have redundancy with each other:
- knockout 1 (but not the other) = muscles develop fine
- knockout both at once = no skeletal muscle
What are the secondary MRFs?
Myogenin (& later MRF4) are expressed during differentiation.
CONTROL DIFFERENTIATION
Promote further differentiation & specialisiation
*knockout either Myogenin or MRF4 and myoblast differentiation is severely affected
Promote expression of muscle-specific genes (ie. MyHC)
MEF2 & SRF
Myocyte enhancement factor 2 (MEF2) & serum response factor (SRF) are other transcription factors (not MRFs) involved in myogenesis.
Can’t initiate myogenesis on their own but contribute to differentiation and maturation of muscle fibres.
Growth factors: what do they affect?
Growth factors (usually soluble) bind to cell surface receptors and induce cellular effects. Involve a variety of intracellular signalling cascades.
Affects:
- myogenesis: by affecting proliferation and/or differentiation
- mature myofibres: by affecting protein metabolism
- hypertrophy (muscle fibre growth) or atrophy (muscle fibre shrinkage)
Growth factors of interest
IGF-1: increased proliferation and differentiation
LIF, IL-6: increased proliferation, same differentiation
FGF, HGF: increased proliferation, decreased differentiation
Insulin, IGF-II: same prolif., increased diff.
TGF-β1 (Myostatin): decreased prolif., increased diff.
What are the embryonic and postnatal roles of myostatin?
Myostatin is traditionally recognised as an inhibitor of differentiation as inhibition of myostatin increases muscle mass. But it’s not inhib of diff, it’s ENHANCEMENT OF PROLIFERATION with myostatin LoF.
H/e diff roles in embryonic vs postnatal.
Myostatin is an essential regulator of the balance between proliferation vs. differentiation of embryonic muscle progenitors.
How does miRNA regulate myogenesis?
miRNA are small non-coding RNAs that play major roles in cell development & differentiation by negatively regulating gene function
Several miRNAs have been shown to be regulated by MRFs
MyomiRs = muscle specific miRNAs
- miR-1/206 family enhances myoblast differentiation
- miR-133 family drives myoblast proliferation
Describe postnatal muscle growth
From birth to adulthood, muscle size increases > 20 fold
But there is no significant change in muscle fibre # after birth
