Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development. Muscle fibers generally form through the fusion of precursor myoblasts into multinucleated fibers called myotubes. In the early development of an embryo, myoblasts can either proliferate, or differentiate into a myotube. What controls this choice in vivo is generally unclear. If placed in cell culture, most myoblasts will proliferate if enough fibroblast growth factor (FGF) or another growth factor is present in the medium surrounding the cells. When the growth factor runs out, the myoblasts cease division and undergo terminal differentiation into myotubes. Myoblast differentiation proceeds in stages. The first stage involves cell cycle exit and the commencement of expression of certain genes. The second stage of differentiation involves the alignment of the myoblasts with one another. Studies have shown that even rat and chick myoblasts can recognise and align with one another, suggesting evolutionary conservation of the mechanisms involved. The third stage is the actual cell fusion itself. In this stage, the presence of calcium ions is critical. Fusion in humans is aided by a set of metalloproteinases coded for by the ADAM12 gene, and a variety of other proteins. Fusion involves recruitment of actin to the plasma membrane, followed by close apposition and creation of a pore that subsequently rapidly widens. Genes and their protein products that are expressed during the process include: myocyte enhancer factors, myogenic regulatory factors, and serum response factor. Expression of skeletal alpha-actin is also regulated by the androgen receptor; steroids can thereby regulate myogenesis.
Overview There are a number of stages (listed below) of muscle development, or myogenesis. Each stage has various associated genetic factors lack of which will result in muscular defects.
Stages
Delamination
Associated Genetic Factors: PAX3 and c-Met Mutations in PAX3 can cause a failure in c-Met expression. Such a mutation would result in a lack of lateral migration. PAX3 mediates the transcription of c-Met and is responsible for the activation of MyoD expression—one of the functions of MyoD is to promote the regenerative ability of satellite cells (described below). PAX3 is generally expressed at its highest levels during embryonic development and is expressed at a lesser degree during the fetal stages; it is expressed in migrating hypaxial cells and dermomyotome cells, but is not expressed at all during the development of facial muscle. Mutations in Pax3 can cause a variety of complications including Waardenburg syndrome I and III as well as craniofacial-deafness-hand syndrome. Waardenburg syndrome is most often associated with congenital disorders involving the intestinal tract and spine, an elevation of the scapula, among other symptoms. Each stage has various associated genetic factors without which will result in muscular defects.
Migration Associated Genetic Factors: c-Met/HGF and LBX1 Mutations in these genetic factors causes a lack of migration. LBX1 is responsible for the development and organization of muscles in the dorsal forelimb as well as the movement of dorsal muscles into the limb following delamination. Without LBX1, limb muscles will fail to form properly; studies have shown that hindlimb muscles are severely affected by this deletion while only flexor muscles form in the forelimb muscles as a result of ventral muscle migration. c-Met is a tyrosine kinase receptor that is required for the survival and proliferation of migrating myoblasts. A lack of c-Met disrupts secondary myogenesis and—as in LBX1—prevents the formation of limb musculature. It is clear that c-Met plays an important role in delamination and proliferation in addition to migration. PAX3 is needed for the transcription of c-Met.
Proliferation Associated Genetic Factors: PAX3, c-Met, Mox2, MSX1, Six, Myf5, and MyoD Mox2 (also referred to as MEOX-2) plays an important role in the induction of mesoderm and regional specification. Impairing the function of Mox2 will prevent the proliferation of myogenic precursors and will cause abnormal patterning of limb muscles. Specifically, studies have shown that hindlimbs are severely reduced in size while specific forelimb muscles will fail to form. Myf5 is required for proper myoblast proliferation. Studies have shown that mice muscle development in the intercostal and paraspinal regions can be delayed by inactivating Myf-5. Myf5 is considered to be the earliest expressed regulatory factor gene in myogenesis. If Myf-5 and MyoD are both inactivated, there will be a complete absence of skeletal muscle. These consequences further reveal the complexity of myogenesis and the importance of each genetic factor in proper muscle development.
Determination Associated Genetic Factors: Myf5 and MyoD One of the most important stages in myogenesis determination requires both Myf5 and MyoD to function properly in order for myogenic cells to progress normally. Mutations in either associated genetic factor will cause the cells to adopt non-muscular phenotypes. As stated earlier, the combination of Myf5 and MyoD is crucial to the success of myogenesis. Both MyoD and Myf5 are members of the myogenic bHLH (basic helix-loop-helix) proteins transcription factor family. Cells that make myogenic bHLH transcription factors (including MyoD or Myf5) are committed to development as a muscle cell. Consequently, the simultaneous deletion of Myf5 and MyoD also results in a complete lack of skeletal muscle formation. Research has shown that MyoD directly activates its own gene; this means that the protein made binds the myoD gene and continues a cycle of MyoD protein production. Meanwhile, Myf5 expression is regulated by Sonic hedgehog, Wnt1, and MyoD itself. By noting the role of MyoD in regulating Myf5, the crucial interconnectedness of the two genetic factors becomes clear. Serum response factor is needed for myogenesis and muscle development. Interaction of SRF with other proteins, such as steroid hormone receptors, may contribute to regulation of muscle growth by steroids.
Differentiation Associated genetic factors: Myogenin, Mcf2, Six, MyoD, and Myf6 Mutations in these associated genetic factors will prevent myocytes from advancing and maturing.
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