Adult myogenesis collectively refers to the process of satellite cell mediated muscle formation. In humans, satellite cell nuclei comprise 4-6% of all basal lamina incapsulated nuclei within muscle, and are able to remain quiescent for years. Satellite cells based on their physiology during the adult myogenic process are grouped into four classes, 1) quiescent, 2) activated, 3) proliferating and 4) differentiating.
Skeletal muscle in the embryo originates from paraxial mesoderm, located laterally to the neural tube. As development progresses, the paraxial mesoderm becomes segmented into epithelial block-like structures known as somites in a rostral to caudal pattern. Somitogenesis occurs in a strict periodic fashion in response to morphogen gradients. FGF and Wnt in the posterior portion of the presomitic mesoderm (PSM) antagonize somitogenesis while retinoic acid (RA) in the anterior PSM promotes epithelisation and somite segmentation. Within the PSM, FGF and Wnt are synthesized only in the most posterior region, such that as the body axis elongates posteriorly, the concentration of these ligands decreases in more anterior regions, resulting in downregulation of their downstream targets. This transition from exposure to high FGF/Wnt to high RA results in differentiation. Indeed, inappropriate exposure of PSM cells to continuously high FGF levels blocks somite segmentation. The region of the PSM where these two gradients meet is referred to as the determination front. The determination front progresses posteriorly as the axis elongates and FGF/Wnt mRNA undergoes progressive decay, and cells located anterior to this position undergo a mesenchymal to epithelial transition.
However, the actual segmentation of the somite from the PSM also relies on the action of a molecular clock that is triggered by Notch and Wnt signaling. Many members of the Notch pathway, including delta, the Hairy and Enhancer of split (HES) transcription factors, hes1 and hes7, and the glycosyl-transferase lunatic fringe exhibit temporal pulses of ex
Transcriptional Regulation of Myogenesis
The myogenic regulatory factors (MRF) family is composed of four basic helix loop helix (bHLH) transcription factors, Myf5, MyoD, MRF4 and myogenin, whose potent myogenic properties are evidenced by their ability to convert other cell types into skeletal muscle. The MRFs bind to E-box target sequences as monomers or as heterodimers in complex with E-proteins and activate muscle gene transcription by coordinating chromatin rearrangements in concert with transcriptional coactivators. The functions of the four MRF proteins have been extensively examined using gene targeting and these studies have revealed a complex and somewhat redundant network controlling myogenesis.
Myf5 is the first MRF to be expressed in the developing embryo and it can be detected as early as stage 3 in the PSM of developing chick embryos or 8.0 days post coitum(d.p.c.) in the mouse somite. The somitic ex
Like Myf5, MyoD is dispensable for normal embryonic muscle development, however, MyoD null mice exhibit elevated levels of Myf5, which is thought to compensate and rescue myogenesis in this context. Interestingly, loss of MyoD does impact on adult muscle regeneration as MyoD mutant mice exhibit impaired regeneration in response to injury, which results from a propensity of MyoD(-/-) satellite cells to undergo self-renewal at the expense of terminal differentiation. A recent high-throughput study aimed at identifying MyoD binding sites revealed, unexpectedly, that MyoD was in fact enriched at thousands of sites within the genome and that binding was associated with increased histone acetylation at these sites. This implies that MyoD has the potential to exert wideranging changes to the epigenome of a cell, resulting in reprogramming to the myogenic lineage.
Until recently, Mrf4 was regarded as being important primarily for terminal differentiation. The Mrf4 knockout mouse exhibited only minimal muscle defects, likely due to compensation by elevated levels of myogenin. However, retrospective analysis of the original Myf5/MyoD compound mutant mouse, which exhibited a complete lack of skeletal muscle, revealed that Mrf4 ex
Myogenin is the second MRF to be activated in the embryo, after Myf5, which is thought to regulate its ex
The Pax family in Myogenesis
Upstream of the MRFs in skeletal myogenesis are members of the Pax family of transcription factors, which have also been implicated in many other developmental processes. They are characterized by their paired box domain and paired-type homeodomain and are classified into groups based on structural characteristics and similarity of ex
The Meox Family: Meox1 and Meox2
Meox1 and Meox2 are homeodomain transcription factors that are expressed in the developing somite. Meox1 ex