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 ).

A , Sketch of an embryo at approximately 41 days shows the myotomes and developing muscular system. B , Transverse section of the embryo illustrates the epaxial and hypaxial derivatives of a myotome. C , Transverse histological section stained with Azan (at approximately the level of the section in B ). Yellow arrow , trapezius; blue arrows , spinalis; red arrows , longissimus; light green arrows , iliocostalis; dark green arrow , levator costarum. D , Similar section of a 7-week embryo shows the muscle layers formed from the myotomes. E , A carmine-stained transverse histological section at the approximate position of the section in D . Red arrows , external oblique; blue arrows , internal oblique; purple arrows , abdominal rectus; green arrows , transverse abdominal.

( C , From Mekonen HK et al. Development of the epaxial muscles in the human embryo, Clin Anat 29:1031, 2016, Figure 8F. E , From Mekonen HK et al: Development of the ventral body wall in the human embryo, J Anat 227:673–685, 2015, Fig. 5 F .)

Genetic regulation of the progression of muscle progenitor cells toward the formation of differentiated skeletal muscle. A , Adult muscle satellite cells progress to form new muscle fiber. MYF5 is shown in the quiescent state (red) to indicate that transcripts are present but not the protein. B , During the progression of somatic cells in myogenesis, expression of PAX3 activates target genes (red) that regulate various stages of this process.

(From Buckingham M, Rigby PW: Gene regulatory networks and transcriptional mechanisms that control myogenesis, Dev Cell 28:225, 2014.)

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.

Gene regulatory networks govern myogenesis in the trunk (A) , the head (B) , and cells that migrate from the hypaxial somite to the forelimb (C) .

(From Buckingham M, Rigby PW: Gene regulatory networks and transcriptional mechanisms that control myogenesis, Dev Cell 28:225, 2014.)

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.

Myotomes

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.

Developing muscular system. A , Drawing of a 6-week embryo shows the myotome regions of the somites that give rise to skeletal muscles. B , Drawing of an 8-week embryo shows the developing trunk and limb musculature.

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.