c h a p t e r 9

Muscular System

With the exception of some smooth muscle tis-

sue (see below), the muscular system develops
from the mesodermal germ layer and consists of
skeletal, smooth, and cardiac muscle. Skeletal
muscle is derived from paraxial mesoderm, which
forms somites from the occipital to the sacral regions
and somitomeres in the head. Smooth muscle differ-
entiates from splanchnic mesoderm surrounding the
gut and its derivatives and from ectoderm (pupillary,
mammary gland, and sweat gland muscles). Cardiac mus-
cle is derived from splanchnic mesoderm surrounding the
heart tube.

Striated Skeletal Musculature

Somites and somitomeres form the musculature of the axial skeleton,

body wall, limbs, and head. From the occipital region caudally, somites
form and differentiate into the sclerotome, dermatome, and two
muscle-forming regions (Fig. 9.1). One of these is in the dorsolateral
region of the somite. It expresses the muscle-specific gene MYO-D and
migrates to provide progenitor cells for limb and body wall (hypomeric)
musculature (Figs. 9.1 and 9.2). The other region lies dorsomedially,
migrates ventral to cells that form the dermatome, and forms the
myotome. This region, which expresses the muscle-specific gene MYF5,
forms epimeric musculature (Figs. 9.1 and 9.2). During differentiation,
precursor cells, the myoblasts, fuse and form long, multinucleated
199
200 Part Two: Special Embryology

Figure 9.1 Stages in the development of a somite. A. Mesoderm cells are arranged
around a small cavity. B. Cells of the ventral and medial walls of the somite lose their
epithelial arrangement and migrate in the direction of the notochord. These cells collec-
tively constitute the sclerotome. Cells at the dorsolateral portion of the somite migrate
as precursors to limb and body wall musculature. Dorsomedial cells migrate beneath
the remaining dorsal epithelium of the somite to form the myotome. C. Cells forming
the myotome continue to extend beneath the dorsal epithelium. D. After ventral exten-
sion of the myotome, dermatome cells lose their epithelial configuration and spread out
under the overlying ectoderm to form dermis.
 Chapter 9: Muscular System 201

Figure 9.2 Expression patterns of genes that regulate somite differentiation. Sonic
hedgehog (SHH), secreted by the notochord and floor plate of the neural tube, causes
the ventral part of the somite to form sclerotome and to express PAX1, which in turn
controls chondrogenesis and vertebral formation. WNT proteins from the dorsal neural
tube activate PAX3, which demarcates the dermomyotome. WNT proteins also direct the
dorsomedial portion of the somite to form epaxial (back) muscles and to express the
muscle-specific gene MYF5. The middorsal portion of the somite is directed to become
dermis by neurotrophin 3 (NT-3) expressed by the dorsal neural tube. Hypaxial (limb
and body wall) musculature is derived from the dorsolateral portion of the somite under
the combined influence of activating WNT proteins and inhibitory BMP-4 protein, which
together activate MYO-D expression.

muscle fibers. Myofibrils soon appear in the cytoplasm, and by the end of
the third month, cross-striations typical of skeletal muscle appear. A similar
process occurs in the seven somitomeres in the head region rostral to the
occipital somites. Somitomeres remain loosely organized structures, however,
never segregating into sclerotome and dermomyotome segments.

Molecular Regulation of Muscle Development

Genes regulating muscle development have recently been identified. BMP4 and
probably FGFs from lateral plate mesoderm, together with WNT proteins from
adjacent ectoderm, signal the dorsolateral cells of the somite to express the
muscle-specific gene MYO-D. BMP4 secreted by overlying ectoderm induces
202 Part Two: Special Embryology

production of WNT proteins by the dorsal neural tube, and these proteins
cause dorsomedial cells of the somite to activate MYF5, another muscle-
specific gene (Fig. 9.2). Both of these genes are members of the MYO-D
muscle-specific family, which also includes the myogenin and MRF4 genes.
MYO-D and MYF5 proteins activate the genes for myogenin and MRF5, which in
turn promote formation of myotubes and myofibers. All MYO-D family mem-
bers have DNA binding sites and act as transcription factors to regulate down-
stream genes in the muscle differentiation pathway.

Patterning of Muscles

Patterns of muscle formation are controlled by connective tissue into which

myoblasts migrate. In the head region these connective tissues are derived
from neural crest cells; in cervical and occipital regions they differentiate from
somitic mesoderm; and in the body wall and limbs they originate from somatic
mesoderm.

Derivatives of Precursor Muscle Cells

By the end of the fifth week prospective muscle cells are collected into two
parts: a small dorsal portion, the epimere, formed from the dorsomedial cells
of the somite that reorganized as myotomes; and a larger ventral part, the
hypomere, formed by migration of dorsolateral cells of the somite (Figs. 9.1B
and 9.3A). Nerves innervating segmental muscles are also divided into a dorsal
primary ramus for the epimere and a ventral primary ramus for the hypomere
(Fig. 9.3B ) and these nerves will remain with their original muscle segment
throughout its migration.
Myoblasts of the epimeres form the extensor muscles of the vertebral
column, and those of the hypomeres give rise to muscles of the limbs and
body wall (Fig. 9.3B). Myoblasts from cervical hypomeres form the scalene,
geniohyoid, and prevertebral muscles. Those from thoracic segments split into
three layers, which in the thorax are represented by the external intercostal, in-
ternal intercostal, and innermost intercostal or transversus thoracis muscle
(Fig. 9.3B ). In the abdominal wall these three muscle layers consist of the ex-
ternal oblique, the internal oblique, and the transversus abdominis muscles.
The ribs cause the muscles in the wall of the thorax to maintain their segmental
character, whereas muscles in the various segments of the abdominal wall fuse
to form large sheets of muscle tissue. Myoblasts from the hypoblast of lum-
bar segments form the quadratus lumborum muscle, and those from sacral
and coccygeal regions form the pelvic diaphragm and striated muscles of the
anus.
In addition to the three ventrolateral muscle layers, a ventral longitudinal
column arises at the ventral tip of the hypomeres (Fig. 9.3B ). This column
 Chapter 9: Muscular System 203

Figure 9.3 A. Transverse section through the thoracic region of a 5-week embryo.
The dorsal portion of the body wall musculature (epimere) and the ventral portion (hy-
pomere) are innervated by a dorsal primary ramus and a ventral primary ramus, respec-
tively. B. Similar to A later in development. The hypomere has formed three muscle
layers and a ventral longitudinal muscle column.

is represented by the rectus abdominis muscle in the abdominal region and

by the infrahyoid musculature in the cervical region. In the thorax, the lon-
gitudinal muscle normally disappears, but is occasionally represented by the
sternalis muscle.

Head Musculature

All voluntary muscles of the head region are derived from paraxial mesoderm
(somitomeres and somites), including musculature of the tongue, eye (except
that of the iris, which is derived from optic cup ectoderm), and that associated
with the pharyngeal (visceral) arches (Table 9.1). Patterns of muscle formation
in the head are directed by connective tissue elements derived from neural
crest cells.

Limb Musculature

The first indication of limb musculature is observed in the seventh week of

development as a condensation of mesenchyme near the base of the limb
buds (Fig. 9.4A). The mesenchyme is derived from dorsolateral cells of the
204 Part Two: Special Embryology

TABLE 9.1 Origins of the Craniofacial Muscles

Mesodermal Origin Muscles Innervation

Somitomeres 1,2 Superior, medial, ventral recti Oculomotor (III)

Somitomere 3 Superior oblique Trochlear (IV)
Somitomere 4 Jaw closing Trigeminal (V)
Somitomere 5 Lateral rectus Abducens (VI)
Somitomere 6 Jaw opening, other 2nd arch Facial (VII)
Somitomere 7 Stylopharyngeus Glossopharyngeal (IX)
Somites 1,2 Intrinsic laryngeals Vagus (X)
Somites 2–5a Tongue Hypoglossal (XII)
a
Somites 2–5 constitute the occipital group (somite 1 degenerates for the most part).

Figure 9.4 A. Myotomes in the head, neck, and thoracic region of a 7-week embryo.
Note the location of the preotic and occipital myotomes and condensation of mes-
enchyme at the base of the limb bud, B. Transverse section through the region of
attachment of the limb bud. Note the dorsal (extensor) and ventral (flexor) muscular
components of the limb.

somites that migrate into the limb bud to form the muscles. As in other regions,
connective tissue dictates the pattern of muscle formation, and this tissue is
derived from somatic mesoderm, which also gives rise to the bones of the limb.
With elongation of the limb buds, the muscle tissue splits into flexor and
extensor components (Fig. 9.4B ). Although muscles of the limbs are segmental
initially, with time they fuse and are then composed of tissue derived from
several segments.
The upper limb buds lie opposite the lower five cervical and upper two
thoracic segments (Fig. 9.5, A and B), and the lower limb buds lie opposite the
lower four lumbar and upper two sacral segments (Fig. 9.5C ). As soon as the
buds form, ventral primary rami from the appropriate spinal nerves penetrate
into the mesenchyme (Fig. 9.6). At first each ventral ramus enters with isolated
dorsal and ventral branches, but soon these branches unite to form large dorsal
 Chapter 9: Muscular System 205

C4
C5
C6

C4
T1
C5
C6 T2

T2
C8

A C7
B

Preaxial side of limb

Postaxial side of limb

Figure 9.5 Limb buds with their segments of origin indicated. With further development
the segmental pattern disappears; however, an orderly sequence in the dermatome
pattern can still be recognized in the adult. A. Upper limb bud at 5 weeks. B. Upper
limb bud at 6 weeks. C. Limb buds at 7 weeks.
206 Part Two: Special Embryology

*
*
*
*
*

Figure 9.6 Scanning electron micrograph of a mouse upper limb bud, showing spinal
nerves entering the limb. Asterisks, spinal ganglia.

and ventral nerves. Thus the radial nerve, which supplies the extensor muscu-
lature, is formed by a combination of the dorsal segmental branches, whereas
the ulnar and median nerves, which supply the flexor musculature, are formed
by a combination of the ventral branches. Immediately after the nerves have
entered the limb buds, they establish an intimate contact with the differentiat-
ing mesodermal condensations, and the early contact between the nerve and
muscle cells is a prerequisite for their complete functional differentiation.
Spinal nerves not only play an important role in differentiation and mo-
tor innervation of the limb musculature, but also provide sensory innervation
for the dermatomes. Although the original dermatomal pattern changes with
growth of the extremities, an orderly sequence can still be recognized in the
adult (Fig. 9.5).

Clinical Correlates

Partial or complete absence of one or more muscles is rather common. One

of the best known examples is total or partial absence of the pectoralis major
muscle (Poland anomaly). Similarly, the palmaris longus, the serratus anterior,
and the quadratus femoris muscles may be partially or entirely absent.
Partial or complete absence of abdominal musculature results in prune-
belly syndrome (Fig. 9.7). Usually the abdominal wall is so thin that organs are
visible and easily palpated. This defect is often associated with malformations
of the urinary tract and bladder.
 Chapter 9: Muscular System 207

Figure 9.7 Prune belly syndrome: a distended abdomen from aplasia of abdominal wall
musculature.

Cardiac Muscle

Cardiac muscle develops from splanchnic mesoderm surrounding the endothe-

lial heart tube. Myoblasts adhere to one another by special attachments that
later develop into intercalated discs. Myofibrils develop as in skeletal muscle,
but myoblasts do not fuse. During later development, a few special bundles
of muscle cells with irregularly distributed myofibrils become visible. These
bundles, the Purkinje fibers, form the conducting system of the heart.

Smooth Muscle

Smooth muscle in the wall of the gut and gut derivatives is derived from
splanchnic mesoderm surrounding the endoderm of these structures. Vascular
smooth muscle differentiates from mesoderm adjacent to vascular endothe-
lium. Sphincter and dilator muscles of the pupil and muscle tissue in the mam-
mary gland and sweat glands originate from ectoderm.
208 Part Two: Special Embryology

Summary

Most muscles arise from the mesoderm. Skeletal muscles are derived
from paraxial mesoderm, including (a) somites, which give rise to mus-
cles of the axial skeleton, body wall, and limbs, and (b) somitomeres,
which give rise to muscles of the head. Progenitor cells for muscle tissues are
derived from the dorsolateral and dorsomedial portions of the somites. Cells
in the dorsolateral portion express MYO-D and migrate to form hypomeric
muscle; cells in the dorsomedial portion express MYF5, migrate ventral to the
dermatome to form the myotome, and ultimately form epimeric musculature.
By the fifth week muscle precursor cells are divided into a small dorsal portion,
the epimere, innervated by a dorsal primary ramus, and a larger ventral por-
tion, the hypomere, innervated by a ventral primary ramus. Myoblasts from
epimeres form extensor muscles of the vertebral column, while those of the
hypomere form limb and body wall musculature. Connective tissue derived
from somites, somatic mesoderm, and neural crest (head region) provide a
template for establishment of muscle patterns. Most smooth muscles and car-
diac muscle fibers are derived from splanchnic mesoderm. Smooth muscles
of the pupil, mammary gland, and sweat glands differentiate from ectoderm.

Problems to Solve

1. Muscle cells are derived from what two regions of the somite? Which region
forms the epimere and which the hypomere? What muscles form from each of
these regions?
2. In examining a newborn female, you note that her right nipple is lower than
the left and that the right anterior axillary fold is nearly absent. What is your
diagnosis?
3. Patterning of muscles is dependent on what type of tissue?
4. How do you explain the fact that the phrenic nerve, which originates from
cervical segments 3, 4, and 5, innervates the diaphragm in the thoracic region?

SUGGESTED READING
Blagden CS, Hughes SM: Extrinsic influences on limb muscle organization. Cell Tiss Res 296:141,
1999.
Brand-Seberi B, Christ B: Genetic and epigenetic control of muscle development in vertebrates. Cell
Tiss Res 296:199, 1999
Braun T, Arnold HH: Myf5 and MyoD genes are activated in distinct mesenchymal stem cells and
determine different skeletal muscle lineages. EMBO J 15:310, 1996.
Chevallier A, Kieny M, Mauger A: Limb-somite relationship: origin of the limb musculature. J Embryol
Exp Morphol 41:245, 1977.
Christ B, Jacob M, Jacob HJ: On the origin and development of the ventrolateral abdominal muscles
in the avian embryo. Anat Embryol 166:87, 1983.
 Chapter 9: Muscular System 209

Cossu G, et al.: Activation of different myogenic pathways: myf5 is induced by the neural tube and
MyoD by the dorsal ectoderm in mouse paraxial mesoderm. Development 122:429, 1996.
Levi AC, Borghi F, Garavoglia M: Development of the anal canal muscles. Dis Colon Rectum 34:262,
1991.
Noden DM: The embryonic origins of avian cephalic and cervical muscles and associated connective
tissues. Am J Anat 168:257, 1983.
Noden DM: Craniofacial development: new views on old problems. Anat Rec 208:113, 1984.
Noden DM: Interactions and fates of avian craniofacial mesenchyme. Development 103:121, 1988.