The muscular system develops from mesoderm , except for the muscles of the iris of the eye, which develop from neuroectoderm (neural crest cells) , and the muscles of the esophagus, which are thought to develop by transdifferentiation from smooth muscle. Myoblasts (embryonic muscle cells) are derived from mesenchyme (embryonic connective tissue). Three types of muscle—skeletal, cardiac, and smooth—are formed during the embryonic period.
MYOD , a member of the family of myogenic regulatory factors, activates transcription of muscle-specific genes, and MYOD is considered an important regulatory gene for the induction of myogenic differentiation. The induction of myogenesis in mesenchymal cells by MYOD depends on the degree of mesenchymal cell differentiation.
Most of the mesenchyme in the head is derived from the neural crest (see Chapter 4 , Fig. 4.10 ), particularly for tissues derived from the pharyngeal arches (see Chapter 9 , Figs. 9.1 H and I and 9.2 ). However, the original mesenchyme in these arches gives rise to the musculature of the face and neck (see Chapter 9 , Table 9.1 ).
Development of Skeletal Muscle
Limb and axial muscles of the trunk and head develop by epitheliomesenchymal transformation from myogenic precursor cells. Studies show that myogenic precursor cells originate from the somatic mesoderm and from the ventral dermomyotome of somites in response to molecular signals from nearby tissues ( Figs. 15.1 and 15.2 ).
The first indication of myogenesis (muscle formation) is elongation of the nuclei and cell bodies of mesenchymal cells as they differentiate into myoblasts. These primordial muscle cells soon fuse to form myotubes: elongated, multinucleated, cylindrical structures.
At the molecular level, these events are preceded by activation and expression of the genes of the MYOD family of muscle-specific, basic helix-loop-helix transcription factors (including MYOD, myogenin [MYOG], MYF5, and myogenic factor 6 [MYF6], formerly called myogenic regulatory factor 4 [MRF4]) in the precursor myogenic cells. Retinoic acid enhances skeletal myogenesis by upregulating the expression of mesodermal markers and myogenic regulatory factors. It has been suggested that signaling molecules from the ventral neural tube and notochord (e.g., SHH) and others from the dorsal neural tube (e.g., WNTs, bone morphogenetic protein 4 [BMP4]) and from overlying ectoderm (e.g., WNTs, BMP4) regulate the beginning of myogenesis and the induction of the myotome ( Fig. 15.3 ). Further muscle growth in the fetus results from the ongoing fusion of myoblasts and myotubes.
During or after fusion of the myoblasts, myofilaments develop in the cytoplasm of the myotubes. Other organelles characteristic of striated muscle cells, such as myofibrils , also form. As the myotubes develop, they become invested with external laminae (layers), which segregate them from the surrounding connective tissue. Fibroblasts produce the perimysium and epimysium layers of the fibrous sheath of the muscle; the endomysium is formed by the external lamina and reticular fibers.
Most skeletal muscles develop before birth, and almost all remaining muscles are formed by the end of the first year. The increase in the size of a muscle after the first year results from increased fiber diameter from the formation of more myofilaments. Muscles increase in length and width to grow with the skeleton. Their ultimate size depends on the amount of exercise that is performed. Not all embryonic muscle fibers persist; many of them fail to establish themselves as necessary units of the muscle and soon degenerate.
Each typical myotome part of a somite divides into a dorsal epaxial division and a ventral hypaxial division (see Fig. 15.1 B ). Every developing spinal nerve divides and sends a branch to each myotome division. The dorsal primary ramus supplies the epaxial division, and the ventral primary ramus supplies the hypaxial division. The myoblasts that form the skeletal muscles of the trunk are derived from mesenchyme in the myotome regions of the somites (see Fig. 15.1 ). Some muscles, such as the intercostal muscles, remain segmentally arranged like the somites, but most myoblasts migrate away from the myotome and form nonsegmented muscles.
Gene-targeting studies in the mouse embryo show that myogenic regulatory factors (MYOD, MYF6, MYF5, and MYOG) are essential for the development of the hypaxial, epaxial, abdominal, and intercostal muscles.
Myoblasts from epaxial divisions of the myotomes form the extensor muscles of the neck and vertebral column ( Fig. 15.4 ). The embryonic extensor muscles derived from the sacral and coccygeal myotomes degenerate; their adult derivatives are the dorsal sacrococcygeal ligaments . Myoblasts from the hypaxial divisions of the cervical myotomes form the scalene, prevertebral, geniohyoid, and infrahyoid muscles (see Fig. 15.4 ). The thoracic myotomes form the lateral and ventral flexor muscles of the vertebral column, and the lumbar myotomes form the quadratus lumborum muscle. The sacrococcygeal myotomes form the muscles of the pelvic diaphragm and probably the striated muscles of the anus and sex organs.
Pharyngeal Arch Muscles
Myoblasts from the pharyngeal arches, which originate from the unsegmented paraxial mesoderm and prechordal plate , form the muscles of mastication, facial expression, pharynx, and larynx as described elsewhere (see Chapter 9 , Fig. 9.6 and Table 9.1 ). These muscles are innervated by pharyngeal arch nerves.
The origin of the extrinsic eye muscles is unclear. They may be derived from mesenchymal cells near the prechordal plate (see Figs. 15.1 and 15.4 ). The mesenchyme in this area is thought to give rise to three preotic myotomes. Myoblasts differentiate from mesenchymal cells derived from these myotomes. Groups of myoblasts, each supplied by its own nerve (cranial nerve [CN] III, CN IV, or CN VI), form the extrinsic muscles of the eye.
Initially there are four occipital (postotic) myotomes ; the first pair disappears. Myoblasts from the remaining myotomes form the tongue muscles, which are innervated by the hypoglossal nerve (CN XII).
The musculature of the limbs develops from myoblasts surrounding the developing bones (see Fig. 15.1 ). The myoblasts form a mass of tissue on the dorsal (extensor) and ventral (flexor) aspects of the limbs. Grafting and gene targeting studies in birds and mammals have demonstrated that the precursor myogenic cells in the limb buds originate from the somites. These cells are first located in the ventral part of the dermomyotome and are epithelial in nature (see Chapter 14 , Fig. 14.1 D ). The cells then migrate into the primordium of the limb.
Molecular signals from the neural tube and notochord induce PAX3, MYOD, and MYF5 expression in the somites. In the limb bud, PAX3 regulates the expression of MET (a migratory peptide growth factor), which regulates migration of the precursor myogenic cells.
Development of Smooth Muscle
Smooth muscle fibers differentiate from splanchnic mesenchyme surrounding the endoderm of the primordial gut and its derivatives (see Fig. 15.1 ). The somatic mesoderm provides smooth muscle in the walls of many blood and lymphatic vessels. The muscles of the iris (sphincter and dilator pupillae) and the myoepithelial cells in mammary and sweat glands are thought to be derived from mesenchymal cells that originate from ectoderm.
The first sign of differentiation of smooth muscle is the development of elongated nuclei in spindle-shaped myoblasts. During early development, additional myoblasts continue to differentiate from mesenchymal cells but do not fuse as in skeletal muscle; they remain mononucleated.
During later development, division of existing myoblasts gradually replaces the differentiation of new myoblasts in the production of new smooth muscle tissue. As smooth muscle cells differentiate, filamentous but nonsarcomeric contractile elements develop in their cytoplasm, and the external surface of each cell acquires a surrounding external lamina. As smooth muscle fibers develop into sheets or bundles, they receive autonomic innervation. Muscle cells and fibroblasts synthesize and lay down collagenous, elastic, and reticular fibers.