DEVELOPMENT OF THE DIAPHRAGM, A SKELETAL MUSCLE ESSENTIAL FOR

MAMMALIAN RESPIRATION
DIAPHRAGM STRUCTURE, FUNCTION, AND EVOLUTION

The diaphragm muscle is composed of two domains. The costal diaphragm is a thin domed
sheet of muscle composed of a radial array of myofibers extending laterally from the ribs and
medially to a central tendon. The crural diaphragm is thicker and located more posteriorly
(dorsally), where it attaches to the vertebrae and surrounds the esophagus and aorta.
Medially, the myofibers of both the costal and crural muscles insert into the central tendon.
The central tendon is located at the apex of the domed diaphragm, holding the diaphragm
muscle domains together. Caudally, it attaches to the liver via the falciform and coronary
ligaments. The tendon is a connective tissue sheet composed of extracellular matrix and the
tendon cells that secrete it. Although less visible in whole mount, each of the myofibers of
the costal and crural muscles is surrounded by muscle connective tissue. The right and left
halves of the diaphragm are innervated by the right and left phrenic motor nerves . These
nerves originate from the cervical nerves, C3-C5, descend along the interior of the vertebrae,
pierce the left and right diaphragm, and spread posteriorly (dorsally) and anteriorly
(ventrally) to innervate myofibers of the crural and costal muscles. The diaphragm is
vascularized by the phrenic, internal thoracic and intercostal arteries.
Figure 1: Major components of the adult diaphragm.

The diaphragm has multiple functions, with its principle function being its critical role in
respiration. During respiration, the actions of the diaphragm are central for inspiration.
Contraction of the diaphragm muscle flattens the dome-shaped diaphragm and central tendon,
which in turn expands the volume of the thoracic cavity, reduces thoracic pressure, and
allows air to flow into the lungs. Interestingly, the diaphragm is not strictly required for
respiration when humans or animals are resting. However, analysis of rats, dogs, and humans
with bilateral diaphragmatic paralysis (in which the phrenic nerves are severed), demonstrate
that the diaphragm is required for respiration and lung ventilation during supine posture
(particularly during rapid-eye-movement sleep) and vigorous activity. In addition to
respiration, the diaphragm (particularly the crural domain) has functional roles in swallowing
and emesis . Finally, the diaphragm also has a passive functional role. The diaphragm serves
as a barrier between the thoracic and abdominal cavities. The importance of this barrier
function is dramatically apparent in newborns with Congenital Diaphragmatic Hernias
(CDH), whereby a weak or incompletely formed diaphragm allows abdominal contents to
herniate into the thoracic cavity and impair lung development.

The presence of a muscularized diaphragm is unique to and, in fact, a defining characteristic

of mammals. While a muscularized diaphragm is unique to mammals, the presence of a
septum separating the lungs from the abdominal viscera is an ancient character, and some
variant of this septum is present in reptiles and birds (but not in fish and amphibians

. In mammals, this septum becomes muscularized to form the diaphragm. It has been
proposed that the diaphragm evolved in mammals as a stabilizer of the abdominal viscera and
an inspiratory muscle.. Together these functions of the diaphragm allowed mammals to
evolve as high-performance homeotherms, capable of concomitant respiration and
locomotion. Thus the question of how the mammalian diaphragm evolved is an important
question. Presumably, developmental innovations were critical for the development of a
muscularized diaphragm, but the molecular and cellular nature of these innovations is
currently unknown.

Congenital Diaphragmatic Hernias

Congenital diaphragmatic hernias (CDH) are common birth defects (1:3000) that often have
severe medical consequences. CDH occurs from a failure of the diaphragm to form properly,
resulting in weak or incomplete regions of muscle. Through these weakened or incomplete
regions the abdominal contents herniate into the thoracic cavity. In turn, the herniated
abdominal contents impede lung development, leading to hypoplastic lungs. Although it is
generally thought that lung hypoplasia simply results from physical impedance of lung
growth by the herniated tissue, some genetic defects associated with CDH directly affect both
diaphragm and lung development. The lung hypoplasia accompanying CDH is the main
cause of the high morbidity and mortality associated with CDH. In spite of medical
intervention, the mortality rate for CDH is 50% and results from respiratory failure. For
patients that survive, chronic respiratory and neurodevelopmental problems are common.
Diaphragmatic hernias vary both in the region of the diaphragm in which they form and in
size. In the majority of cases (90%), hernias form in the posterior lateral diaphragm, and these
posterolateral hernias (termed Bochdalek hernias) develop predominantly on the left side of
the diaphragm. Posterolateral hernias are the form of CDH most commonly associated with
lung hypoplasia because the abdominal contents herniate into the posterior pleural cavity
where the developing lungs are forming. Hernias also form in anterior regions (termed
Morgagni hernias) or in the central tendon (termed central hernias). However, hernias in
these regions generally have less severe consequences. Diaphragmatic hernias also vary in
size, with larger hernias having more critical impacts on health, while smaller hernias may be
asymptomatic.
Figure 3: Major types of congenital diaphragmatic hernias.

SUMMARY

I. The diaphragm is a musculotendinous, dome-shaped partition between the thoracic and abdominal
cavities and develops from 4 major structures
A. THE SEPTUM TRANSVERSUM (most important component) forms the central tendon and is
first seen as a thick mesodermal plate cranial to the pericardial cavity between the base of the
thoracic cavity and the stalk of the yolk sac
1. The septum does not separate the thoracic and abdominal cavities entirely, but after
the headfold forms (week 4), it becomes a thick incomplete partition between the
cavities with an opening on each side of the gut, the pleural canals
2. The septum fuses dorsally with the primitive mediastinal mesenchyme below the
esophagus and later with the pleuroperitoneal membranes
B. PLEUROPERITONEAL MEMBRANES fuse with the dorsal mesentery of the esophagus and with
the dorsal part of the septum transversum to complete the partition between the thoracic and
abdominopelvic cavities to form the primitive diaphragm. They represent only a small portion
of the final adult structure
C. THE DORSAL ESOPHAGEAL MESENTERY (mesoesophagus) fuses with both A and This
mesentery forms the median portion of the diaphragm. The crura of the diaphragm develop
from muscle fibers which grow into the esophageal mesentery
D. THE BODY WALL: during weeks 9 to 12, the pleural cavities enlarge and invade the lateral
body walls. Body wall tissue, at this time, splits off medially to form the peripheral parts of the
diaphragm outside that formed by the membranes (B)
1. Extensions of the pleural cavities into the body walls form the costodiaphragmatic
recesses
II. Innervation and position of the diaphragm
A. DURING WEEK 4, THE SEPTUM TRANSVERSUM lies opposite the upper cervical somites, and
during week 5, nerves from the cervical spinal segments, C3, C4, and C5 grow into the septum
and form the phrenic nerve. These nerves pass to the septum via the pleuropericardial
membrane, thus, the nerves lie in the fibrous pericardium
B. RAPID GROWTH OF THE DORSAL EMBRYO BODY compared to its ventral part results in an
apparent descent of both diaphragm and nerves, by week 6, to thoracic somite level
C. BY WEEK 8, the dorsal part of the diaphragm lies at the level of the first lumbar vertebrae,
thus, its nerve has been carried down with it from the cervical region
III. Congenital malformations
A. CONGENITAL DIAPHRAGMATIC HERNIA: a common malformation in the newborn seen in
1/2200 births and usually as a posterolateral defect of the diaphragm
1. Usually results as a defective formation and/or fusion of the pleuroperitoneal
membrane(s) which normally separate(s) the pleural and peritoneal cavities
2. Defect is usually unilateral with a large opening (foramen of Bochdalek) in the
posterolateral part of diaphragm. It is seen more often on the left as a result of an
earlier closure of the right pleuroperitonea1 opening
3. If the pleuroperitoneal membrane is not fused when the intestines return to the
abdomen from the umbilical cord (week 10), the intestines may pass into the chest
4. Occasionally see stomach, spleen, cecum, appendix, and parts of colon in the chest
cavity. If present at birth, may interfere with respiration
5. Heart and mediastinum are often displace Lungs are small and hypoplastic
B. CONGENITAL HIATAL HERNIA: rare; abdominal viscera herniate through a large esophageal
hiatus or opening. Usually an acquired lesion seen in adult life
C. ESOPHAGEAL HERNIA: if esophagus is shorter than normal, part of stomach may appear in the
thorax and be constricted as it passes through the enlarged esophageal hernia
D. RETROSTERNAL OR PARASTERNAL HERNIA (of Morgagni): a rare defect between sternum and
sternocostal parts of diaphragm. A small peritoneal sac with intestinal loops often seen in chest
E. CONGENITAL EVENTRATION OF DIAPHRAGM: rare; half of diaphragm has defective muscles
and balloons up into chest cavity. Upward displacement of abdominal contents