Building muscle: molecular regulation of myogenesis

Abstract

The genesis of skeletal muscle during embryonic development and postnatal life serves as a paradigm for stem and progenitor cell maintenance, lineage specification, and terminal differentiation. An elaborate interplay of extrinsic and intrinsic regulatory mechanisms controls myogenesis at all stages of development. Many aspects of adult myogenesis resemble or reiterate embryonic morphogenetic episodes, and related signaling mechanisms control the genetic networks that determine cell fate during these processes. An integrative view of all aspects of myogenesis is imperative for a comprehensive understanding of muscle formation. This article provides a holistic overview of the different stages and modes of myogenesis with an emphasis on the underlying signals, molecular switches, and genetic networks.

Figure 1.

Embryonic myogenesis. (A) Embryonic day 10.5 (E10.5) mouse embryo carrying an Myf5 lineage tracer that induces irreversible expression of a red fluorescent protein. Expression can be observed in the presomitic mesoderm, the somites, and in several head structures. (B) Illustration of the morphogen gradients along the rostral–caudal axis of the embryo. (C) Schematic of transverse sections through the embryo at early (i) and late (ii) stages of somitogenesis. (Ci) Morphogens secreted from various domains in the embryo specify the early somite to form the sclerotome (SC) and dermomyotome (DM). Wnts secreted from the dorsal neural tube (NT) and surface ectoderm (SE) along with bone morphogenetic protein (BMP) from the lateral plate mesoderm maintain the undifferentiated state of the somite, whereas Sonic hedgehog (Shh) signals from the neural tube floor plate and notochord (NC) to induce the formation of the sclerotome. (Cii) As the sclerotome segregates, muscle progenitor cells (MPCs) from the dorsomedial (DML) and ventrolateral (VLL) lips of the dermomyotome mature to give rise to the myotome (MY). At the level of the limb bud, Pax3-dependent migrating MPCs delaminate from the ventrolateral lips to later give rise to limb muscles.

Figure 2.

Hierarchy of transcription factors regulating progression through the myogenic lineage. Muscle progenitors that are involved in embryonic muscle differentiation skip the quiescent satellite cell stage and directly become myoblasts. Some progenitors remain as satellite cells in postnatal muscle and form a heterogeneous population of stem and committed cells. Activated committed satellite cells (Myoblasts) can eventually return to the quiescent state. Six1/4 and Pax3/7 are master regulators of early lineage specification, whereas Myf5 and MyoD commit cells to the myogenic program. Expression of the terminal differentiation genes, required for the fusion of myocytes and the formation of myotubes, are performed by both myogenin (MyoG) and MRF4.

Figure 3.

Schematic of skeletal muscle and the satellite cell niche. (A) Satellite cells reside along the host muscle fiber and are marked by Pax7 expression (red); nuclei (blue); cytoplasm (green). (B) Satellite cells (arrow) marked by Pax7 (green) are found beneath the basal lamina (red) that surrounds each muscle fiber. In mature muscle, they are always associated with a myonucleus (arrowhead) and are in close proximity to local capillaries (empty arrowhead). (C) Representation of skeletal muscle and the satellite cell niche. Molecular signals within the niche govern the behavioral response of satellite cells in maintaining quiescence or activation during injury.

Figure 4.

Asymmetric versus stochastic modes of satellite cell division. As determined by lineage tracing, 10% of adult satellite cells have never expressed Myf5 and are referred to as “satellite stem cells.” (A) Satellite stem cells (arrow) undergo asymmetric division in an apical–basal orientation in which the daughter cell that is detached from the basal lamina up-regulates Myf5 and the fluorescent lineage tracer YFP (arrowhead). Pax7 (red); YFP (green); nuclei (blue). (B,C) In the stochastic mode of division, both types of satellite cells divide planar along the host fiber and give rise to two identical daughter cells. (D) Model of apical-basal divisions leading to an asymmetric outcome. Opposing signals from the basal lamina and the myofiber control the orientation of DNA spindles and the asymmetric cosegregation of proteins and DNA strands. Post-cytokinesis, daughter cells continue to be subjected to different signals leading to asymmetric cell fates. (E) Planar divisions lead to the symmetric expansion of cells. Signals such as the Wnt7a–PCP pathway drive the planar orientation of DNA spindles. Daughter cells in this outcome remain attached to the host fiber and the basal lamina, thus receiving similar signals, and maintain identical cell fates.