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While continued longitudinal growth of bones depends on adequate Successive layers of bone are deposited on the surface of the previous
levels of GH, effective remodelling to achieve a mature shape also layer as cohorts of osteoblasts become embedded (as osteocytes) in the
requires the action of thyroid hormones. Moreover, growth and skeletal matrix they secrete, until the most central lamella is close to the blood
maturity are closely related to endocrine activities of the ovaries, testes vessel at the axis of the cylinder. The ‘closing cone’ (see Fig. 5.26) may
and suprarenal cortices. High oestrogen levels increase deposition of contain 4000 osteoblasts per mm2. In this way, the walls of resorption
endosteal and trabecular bone; conversely, osteoporosis in postmeno canals are lined with new lamellar matrix and the vascular channels are
pausal women reflects reduced ovarian function. In men, fluctuations progressively narrowed. A hypermineralized basophilic cement (or
in the rate of growth, and the timing of skeletal maturation, depend on growthreversal) line marks the edge of a new osteon, indicating the
circulating levels of suprarenal and testicular androgens. In hypogonad border between the resorptive activity of the cutting cone and the bony
ism, growthplate fusion is delayed and the limbs therefore elongate matrix not remodelled by this activity. Remnants of the circumferential
excessively; conversely, in hypergonadism, premature fusion of the epi lamellae of old osteons form interstitial lamellae between newer
physes results in diminished stature. osteons (see Fig. 5.17A).
The remodelling unit in cancellous bone, equivalent to the second
Bone remodelling ary osteon of compact bone, is the basic (or bony) structural unit; it
has an average thickness of 40–70 µm and an average length of 100 µm,
but may be more extensive and irregular in shape. Separate structural
Stiff materials (including bone) are vulnerable to the accumulation of
units can sometimes be visualized in microradiographs because of dif
microdamage during repeated loading. In metals this can result in crack


ferences in their age and extent of mineralization (Farlay et al 2005).
propagation and ‘fatigue failure’. Bone reduces the risk of such failure
Adult bone shape and mass are partly determined by genetic inherit
by periodically renewing itself, one small region of tissue at a time. This
ance (Sigurdsson et al 2008). However, the pattern and extent of
process is referred to as ‘remodelling’ because the volume and orienta
remodelling are largely dictated by the mechanical loading applied to
tion of newly replaced matrix are not necessarily the same as the old;
the bone. Bone resorption occurs when muscle or gravitational forces
instead, bone takes this opportunity to adapt its mass and architecture
are reduced, as occurs in bed rest, or in zero gravity conditions in space
to prevailing mechanical demands. Remodelling affects the local
(Shackelford et al 2004). Reduced activity in old age is another major
balance between resorption and deposition of bone. Its primary purpose
cause of bone loss. The rate of remodelling decreases with age, which
is to renew bone rather than increase its mass, and the process continues
means that numbers of osteons and osteon fragments can be used to
throughout life, replacing approximately 10% of bone each year in
estimate the age of skeletal material at death. Conversely, increased
adults (Brandi 2009).
sporting or occupational loading of the skeleton can cause bone hyper
Internal remodelling continuously supplies young osteons with
trophy, as exemplified by the 35% increase in cortical thickness in the
labile calcium reserves, and provides a malleable bony architecture that
racket arm of elite tennis players (Jones et al 1977). Bones appear to
is responsive to changing patterns of stress. A boneremodelling unit
respond to the maximum deformation they experience (see Fig. 5.68),
consists of an advancing cutting cone and a closing cone. Activated
rather than to cumulative load. Bone subjected to constant pressure can
osteoclasts form a cutting cone that excavates a cylindrical tunnel of
actually resorb, a response that underpins much orthodontic treatment,
bone (resorption canal) and advances ahead of a central growing blood
because teeth can be made to migrate slowly through alveolar bone by


vessel at a rate of 50 µm/day. A cutting cone is typically 2 mm long and
the application of steady lateral or medial pressure.
takes 1–3 months to form; a similar period is required to create the
new (secondary) osteon by completing the closing cone (Fig. 5.26).
Osteoblasts follow the osteoclasts, filling in the space created with Growth of individual bones
new osteoid, starting at the peripheral surface or walls of the tunnel.
Ossification centres appear over a long period during bone growth:
many in embryonic life, some in prenatal life, and others well into the
postnatal growing period. Ossification centres are initially microscopic
but soon become macroscopic, which means that their growth can then
Developing be followed by radiological and other scanning techniques.
resorption
Some bones, including carpal, tarsal, lacrimal, nasal and zygomatic
canal
Time bones, inferior nasal conchae and auditory ossicles, ossify from a single
Cutting
cone centre, which may appear between the eighth intrauterine week and the
Osteoclast tenth year: a wide interval for studying growth or estimating age. Most
bones ossify from several centres, one of which appears in the centre
of the future bone in late embryonic or early fetal life (seventh week to
Resorption
canal fourth month). Ossification progresses from the centres towards the
Reversal
ends, which are still cartilaginous at birth (Fig. 5.27). These terminal
zone
regions ossify from separate centres, which are sometimes multiple, and
which appear between birth and the late teens; they are therefore sec
Fibroblast
ondary to the earlier primary centre from which much of the bone
ossifies. This is the pattern in long bones, as well as in some shorter
bones such as the metacarpals and metatarsals, and in the ribs and
clavicles.
At birth, a bone such as the tibia is typically ossified throughout its
diaphysis from a primary centre that appears in the seventh intrauterine
week, whereas its cartilaginous epiphyses ossify from secondary centres.
Osteoblast
As the epiphyses enlarge, almost all the cartilage is replaced by bone,
Closing Forming


cone osteon except for a specialized layer of articular (hyaline) cartilage that persists
at the joint surface, and a thicker zone between the diaphysis and epi
physis. Persistence of this epiphysial growth plate, or growth cartilage,
allows increase in bone length until the usual dimensions are reached,
by which time the epiphysial plate has ossified. The bone has then
Quiescent
osteoblast reached maturity. Coalescence of the epiphysis and diaphysis is fusion,
the amalgamation of separate osseous units into one.
Completed Many long bones have epiphyses at both their proximal and their
osteon distal extremities. Metacarpals, metatarsals and phalanges have only
Blood vessel
one epiphysis. Typical ribs have epiphyses for the head and articular
tubercle and one for the nonarticular area. The costal cartilages repre
sent the unossified hyaline cartilage of the developing rib and therefore
Fig. 5.26 Bone remodelling. Longitudinal and cross-sections of a time do not display epiphyses. Epiphysial ossification is sometimes complex,
line illustrating the formation of an osteon. Osteoclasts cut a cylindrical e.g. the proximal end of the humerus is wholly cartilaginous at birth
channel through bone. Osteoblasts follow, laying down bone on the and subsequently develops three centres during childhood, which coa
surface of the channel until matrix surrounds the central blood vessel of lesce into a single mass before they fuse with the diaphysis. Only one
the newly formed osteon (closing cone of a new osteon). of these centres forms an articular surface; the others form the greater


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junctions, at which bone is bonded to bone through cartilage, through
out the active years of childhood and adolescence.
Forces at growth cartilages are largely compressive but with an
element of shear. Interference with epiphysial growth may occur as a
result of trauma but more frequently follows disease; the resulting
changes in trabecular patterns of bone are visible radiographically as
dense transverse lines of arrested growth (Harris’s growth lines). Several
such lines may appear in the limb bones of children afflicted by suc
A
cessive illnesses.
Variation in skeletal development occurs between individuals, sexes
and possibly also races. The timing rather than the sequence of events
varies, and females antedate males in all groups studied. Differences
that are perhaps insignificant before birth may be as great as 2 years in
adolescence.
JOINTS
B
Joints are the regions of the skeleton where two or more bones meet
Fig. 5.27 A, A radiograph of a neonatal arm. Ossification from primary and articulate. These junctions are supported by a variety of soft tissue
centres is well advanced in all of the limb bones except the carpals, structures, and their prime functions are either to facilitate growth or
which are still wholly cartilaginous. The gaps by which individual elements to allow movement between bones. The simplest classifications of joints
appear to be separated are filled by radiolucent hyaline cartilage, in which relate to either the range of movement possible or the nature of the
epiphysial or carpal ossification will subsequently occur. Note the flaring intervening soft tissues; there is no satisfactory single classification. Free
contours, narrow midshaft and relatively expanded metaphyses of the movement occurs at synovial joints, whereas restricted movement
long bones, and the proportions of the limb segments – in particular, the occurs at synarthroses, which can be subdivided into fibrous and carti
relatively large hand – that are characteristic of this age. B, The bones laginous joints. The general characteristics of each type of joint will be
and cartilages of a neonatal left arm. Compare the radiolucent areas in considered next. Features that are specific to individual joints are dis


the radiograph (A) with the preserved cartilaginous epiphyses and carpal cussed in the relevant topographical chapters.
elements in this specimen. (B, Prepared by Michael C.E. Hutchinson;
photographed by Kevin Fitzpatrick on behalf of GKT School of Medicine,
London.) FIBROUS JOINTS
Bones in fibrous joints are joined by fibrous connective tissue that
allows little movement. Three definable subtypes are sutures, gom
and lesser tubercles, which give muscular attachments. Similar compos phoses and syndesmoses (Fig. 5.28).
ite epiphyses occur at the distal end of the humerus and in the femur,
ribs and vertebrae. Suture
Many cranial bones ossify from multiple centres. The sphenoid,
temporal and occipital bones are almost certainly composites of
Sutures are restricted to the skull (see Ch. 27 for descriptions of indi
multiple elements in their evolutionary history. Some show evidence
vidual sutures). In a suture, the two bones are separated by a layer of
of fusion between membrane and cartilage bones that unite during
membranederived connective tissue. The sutural aspect of each bone
growth.
is covered by a layer of osteogenic cells (cambial layer) overlaid by a
If bone growth rate were uniform, ossification centres would appear
capsular lamella of fibrous tissue that is continuous with the perios
in a strict descending order of bone size. However, disparate rates of
teum on both the endo and ectocranial surfaces. The region between
ossification occur at different sites and do not appear to be related to
the capsular coverings contains loose fibrous connective tissue and
bone size. The appearance of primary centres for bones of such different
decreases with age, so that the osteogenic surfaces become apposed. On
sizes as the phalanges and femora are separated by, at most, a week of
completion of growth, many sutures synostose and are obliterated.
embryonic life. Those for carpal and tarsal bones show some correlation
Synostosis occurs normally as the skull ages; it can begin in the early
between size and order of ossification, from largest (calcaneus in the
twenties and continues into advanced age. A schindylesis is a special


fifth fetal month) to smallest (pisiform in the ninth to twelfth postnatal
ized suture in which a ridged bone fits into a groove on a neighbouring
year). In individual bones, succession of centres is related to the volume
element, e.g. where the cleft between the alae of the vomer receives the
of bone that each centre produces. The largest epiphyses, e.g. the adja
rostrum of the sphenoid (see Fig. 5.28).
cent ends of the femur and tibia, are the earliest to begin to ossify
(immediately before or after birth) and are of forensic interest. At epi Gomphosis
physial plates, the rate of growth is initially equal at both ends of those
bones that possess two epiphyses. However, experimental observations
A gomphosis is a pegandsocket junction between a tooth and its
in other species have revealed that one epiphysis usually grows faster
socket, where the two components are maintained in intimate contact
than the other after birth. Since the fastergrowing end also usually fuses
by the collagen of the periodontium connecting the dental cement to
later with the diaphysis, its contribution to length is greater. Though
the alveolar bone. Strictly speaking, a gomphosis is not an articulation
faster rate has not been measured directly in human bones, later fusion
between two skeletal structures.
has been documented radiologically. The more active end of a long
limb bone is often termed the growing end but this is a misnomer.
Syndesmosis
The rate of increase in stature, which is rapid in infancy and again
at puberty, demonstrates that rates of growth at epiphyses vary. The
spurt at puberty, or slightly before, decreases as epiphyses fuse in post A syndesmosis is a truly fibrous connection between bones. It may be
adolescent years. represented by an interosseous ligament (e.g. the interosseous mem
Growth cartilages do not grow uniformly at all points, which pre brane between the radial and ulnar shafts), a slender fibrous cord, or a
sumably accounts for changes such as the alteration in angle between denser fibrous membrane (e.g. the posterior region of the sacroiliac


the humeral shaft and its neck. The junctions between epiphysis and joint: see Fig. 5.28).
diaphysis at growth plates are not uniformly flat on either surface.
Osseous surfaces usually become reciprocally curved by differential
growth, and the epiphysis forms a shallow cup over the convex end of CARTILAGINOUS JOINTS
the shaft, with cartilage intervening: an arrangement that may resist
shearing forces at this relatively weak region. Reciprocity of bone sur Cartilaginous joints may be classified as primary (synchondrosis) or
faces is augmented by small nodules and ridges, as can be seen when secondary (symphysis), depending on the nature of the intervening
the surfaces are stripped of cartilage. These adaptations emphasize the cartilage. While the distinction between fibrous and cartilaginous
formation of many immature bones from several elements held together joints is usually clear, some degree of admixture can occur in which
by epiphysial cartilages. Most human bones exhibit these complex either a predominantly fibrous articulation contains occasional islands


Joints
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Suture Syndesmoses
Uniting layer Dermal bone
Interosseous
ligaments
Cambial Middle Capsular Cambial
Sacrum
Layers of sutural ligament
Synovial joint Syndesmosis
Hip bones
Radius Ulna
Gomphosis Interosseous membrane
(dento-alveolar joint)
Schindylesis
(ridge and groove)
Sphenoidal
rostrum
Vomer
Fig. 5.28 Examples of the principal varieties of fibrous
joints, each shown in section.
of cartilage, or a predominantly cartilaginous articulation contains All symphyses occur in the midline (mandibular, manubriosternal,
aligned dense bundles of collagen. These joints tend to be less rigid pubic and intervertebral) and all except the mandibular symphysis
than the fibrous articulations and some permit restricted movement occur in the postcranial skeleton and resist synostosis. The mandibular
(Figs 5.29–5.30). symphysis (symphysis menti) is histologically different from the other
symphyses; however, the widespread use of this descriptive term ensures
Primary cartilaginous joints that it remains, perhaps inappropriately, within this category.
The concept that synchondroses are temporary and concerned with
growth, whereas symphyses are permanent and concerned with move
Primary cartilaginous joints or synchondroses occur where advancing
ment, is an oversimplification and only partly correct. Both types of
centres of ossification remain separated by an area of hyaline (but non
joint must be strong, both are sites at which growth occurs, and both
articular) cartilage. They are present in all postcranial bones that form
contribute either directly or indirectly to the total movement patterns
from more than one centre of ossification. Since hyaline cartilage
of the parts involved. Movements that occur at a symphysis often
retains the capability to ossify with age, synchondroses tend to synos
depend on more than the mechanical properties of the fibrocartilagi
tose when growth is complete. Primary cartilaginous joints are almost
nous pad or disc, e.g. movements between vertebrae depend not only
exclusively associated with growth plates (see above).


on the deformability of the intervertebral disc but also on the morphol
ogy of the apophysial joints and the properties of associated ligaments
Secondary cartilaginous joints
(Adams et al 2013).
The prominent role of synchondroses in skeletal growth is widely
Secondary cartilaginous joints, or symphyses, are largely defined by the recognized, whereas growth of symphyses has received less attention.
presence of an intervening pad or disc of fibrocartilage interposed Symphysial growth may, for convenience, be considered from two inter
between the articular (hyaline) cartilage that covers the ends of two related aspects: namely, intrinsic growth of the fibrocartilaginous disc,
articulating bones. The pad or disc varies from a few millimetres to over and growth of the hyaline cartilaginous plates into which endochondral
a centimetre in thickness, and the whole region is generally bound by ossification progresses.
strong, tightly adherent, dense connective tissues. Collagenous liga
ments extend from the periostea of the articulating bones across the
symphysis. The ligaments blend with the hyaline and fibrocartilaginous SYNOVIAL JOINTS
perichondria but do not form a complete capsule. They contain plex
uses of afferent nerve terminals, which also penetrate the periphery of These are freely moving joints in which the articulating bony surfaces
the fibrocartilage. The combined strength of the ligaments and fibrocar are covered in smooth (hyaline) articular cartilage and separated by a
tilage can exceed that of the associated bones. A symphysis is designed film of viscous synovial fluid that serves as a lubricant (Fig. 5.31). Joint
to withstand a range of stresses (compression, tension, shear, bending stability is provided by a fibrous capsule (which usually has intrinsic
and torsion) but the range of movement is generally limited, both by ligamentous thickenings), and often by internal or external accessory
the physical nature of the articulation and by adjacent bones. Tears are ligaments. Synovial fluid, which also aids metabolite transport to cells
usually the result of sudden stresses that occur when the body is in an in the articular cartilages, is synthesized by the synovial membrane that
inappropriate posture. lines the joint capsule.


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A Synchondroses
Epiphysis Primary centre
Endochondral (secondary centre) e.g. basisphenoid
bone Endochondral
ossification
Hyaline Cartilaginous
cartilage growth and
transformation
Endochondral Endochondral
bone ossification
Metaphysis Primary centre Fate of
(primary centre) e.g. basioccipital synchondrosis
Varieties: Asymmetric Symmetric Synostosis
B Symphyses Terminal growth plate Synchondrosis Anular epiphysis Synostosis of
of hyaline cartilage anular epiphysis
Fibrocartilaginous Nucleus
anulus pulposus Fibrocartilage invades nucleus Obliteration of nucleus pulposus
First decade 15–25 years Mature (presacral) symphysis
Fig. 5.29 Examples of varieties of cartilaginous joints (see also Fig. 5.30). A, A sectional view of the principal tissues involved, more detailed architecture
and main growth patterns of symmetrical and asymmetrical synchondroses. Lesser degrees of asymmetry occur in some locations. Synostosis is the
normal fate of almost all synchondroses when endochondral growth has ceased. B, Intervertebral symphyses (presacral), shown in section, displaying
age-related changes. Partial or complete synostosis is the normal fate of sacral and coccygeal symphyses.
Body of sternum Articular surfaces
Sternochondral synovial joints with fibrocartilaginous articular Articular cartilage comprises a specialized type of hyaline cartilage,
surfaces (sometimes synarthroses with fibrocartilage bond)
reflecting its origin as part of the cartilaginous ‘model’ of bone in
embryonic life. Exceptions include the sternoclavicular, acromioclavicu
lar and temporomandibular joints, where articulating surfaces are
Interchondral synovial joints
covered by dense fibrous tissue containing isolated groups of chondro
cytes with little proteoglycan in their surrounding matrix, presumably
reflecting their formation by intramembranous ossification.
The most superficial cartilage, directly adjacent to the synovial fluid,


is an acellular layer approximately 3 µm thick, which contains fine col
lagen fibrils running parallel to the surface. It functions as an elastic
and protective ‘skin’ for the underlying tissue, and can appear to recoil
under tension if the cartilage is damaged. The deformability of articular
cartilage enables opposing cartilage surfaces to flatten slightly at their
area of contact, increasing contact area and decreasing contact stress
(see Fig. 5.57). This loaddistributing property of articular cartilage
Xiphoid process depends on the congruence of opposing joint surfaces (see Fig. 5.61).
Slight undulations in the surface trap synovial fluid so that fluidfilm
lubrication is possible under most circumstances; effectively, the bones
Interchondral ligaments
‘aquaplane’ on each other (Fig. 5.60). This ensures very low friction
(interchondral
and, consequently, low wear of the cartilage.
syndesmoses)
The acellular surface layer is coated with a large glycoprotein,
lubricin, which projects from the surface so that a hydrophobic region
of the molecule lies in the joint space, where it repels its counterpart
on the opposing articular surface. In this way, lubricin acts in the
manner of a lubricant such as grease to reduce friction and wear of the
surface zone. This ‘boundary lubrication’ mechanism becomes impor
tant when the fluid film has been squeezed out, e.g. after sustained
forceful loading of the joint, and loss of lubricin can lead to cartilage
degeneration (Waller et al 2013). Transmission electron microscopy
shows this lubricant layer as an interrupted electrondense surface coat
0.03–0.1 µm thick. Synovial fluid and membranous debris, the product
Costochondral synarthroses with adherent fibrocartilaginous plate; of chondrocytic necrosis, may contribute to this surface coat, which is
periosteum and perichondrium are continuous transient in nature. The ‘lamina splendens’, a structure that appears as
a bright line at the free surface of articular cartilage when oblique sec
Fig. 5.30 Less common interchondral and osseochondral junctions: see


text for other locations. General periosteum and perichondrium omitted. tions are examined by negative phase contrast microscopy, may be a


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A Simple B Compound C Complex
Synovial membrane
Capsule
Articular cartilage
Articular cartilage Synovial membrane
Synovial cavity
Articular disc
Synovial cavity
Capsule
Fig. 5.31 Synovial joints, some main structural features and one elementary type of classification: A, simple; B, compound; C, complex joints. For
clarity, the articular surfaces are artificially separated. A and C are purely diagrammatic and not related to particular joints. B, however, is a simplified
representation of some features of an elbow joint; the complicated contours due to the olecranon, coronoid and radial fossae, and profiles of articular fat
pads have been omitted for clarity.
microscopical artefact at the border between regions of different refrac
tive index, rather than an anatomically distinct surface layer. Deeper
zones of articular cartilage are described on page 83.
With advancing age, undulations on the articular surfaces deepen
and develop minute, ragged projections, perhaps as a consequence of
wear and tear. These changes are extremely slow in healthy joints, but A
are accelerated in pathologically ‘dry’ joints and where synovial fluid
viscosity is altered. SM
C
Fibrous capsule
S
A fibrous capsule completely encloses each synovial joint except where
it is interrupted by synovial protrusions (see descriptions of individual
joints for details). It is composed of interlacing bundles of parallel fibres A
of collagen type I, and is attached continuously round the ends of the
articulating bones. In small bones this attachment is usually near the
periphery of the articular surfaces, but in long bones it varies consider
ably, and part or all of the attachment may be a significant distance
from the articular surface. The joint capsule is perforated by vessels and Fig. 5.32 A section of a synovial joint and its associated highly vascular
nerves, and may contain apertures through which synovial membrane synovial membrane in a human fetal hand. The two articular cartilage
protrudes as bursae. It is lined by a synovial membrane that also covers surfaces (A, arrows) are separated on the right by a layer of synovial fluid


all nonarticular surfaces (bones, tendons and ligaments) that lie partly (S) secreted by the synovial membrane (SM), which extends a short
or wholly within the fibrous capsule. Where a tendon is attached to distance into the joint space from the capsule (C).
bone inside a synovial joint, an extension of the synovial membrane
usually accompanies it beyond the capsule. Some extracapsular tendons
are separated from the capsule by a synovial bursa continuous with the sufficiently constant to be named, e.g. the alar folds and ligamentum
interior of the joint. These protrusions are potential routes for the mucosum of the knee. Synovial villi are more numerous near articular
spread of infection into joints. margins and on the surfaces of folds and fringes, and become promi
A fibrous capsule usually exhibits local thickenings of parallel nent in some pathological states.
bundles of collagen fibres, called capsular (intrinsic) ligaments, and Accumulations of adipose tissue (articular fat pads) occur within the
named by their attachments. Some capsules are reinforced or replaced synovial membrane in many joints. These pads, and also synovial folds
by tendons of nearby muscles, or expansions from them. Accessory liga and fringes, are deformable cushions that occupy potential spaces and
ments are distinct structures, and may be located inside or outside the irregularities in joints that are not wholly filled by synovial fluid. During
joint capsule. All ligaments, although stiff in tension, are pliant in movement they accommodate to the changing shape and volume of
bending. They can rebound elastically from being stretched by up to the irregularities, a function they share with intraarticular discs and
10–15%, and are protected from injury by reflex contraction of appro menisci. They also increase the area of synovial membrane, and may
priate muscles. They do little to resist normal movements but become help to spread synovial fluid over the articular surfaces.
taut at the end of each normal range of movement. The synovial membrane has two layers: a highly cellular intimal
layer resting on a fibrous and vascular subintimal layer (subsynovial
Synovial membrane
tissue). The subintima is often composed of loose, irregular connective


tissue, but also contains organized collagen and elastin fibres lying
Synovial membrane lines the fibrous joint capsule and exposed osseous parallel to the membrane surface, interspersed with occasional fibro
surfaces, intracapsular ligaments, bursae and tendon sheaths (Fig. blasts, macrophages, mast cells and fat cells. The elastic component
5.32). It does not cover intraarticular discs or menisci, and stops at the may prevent formation of redundant folds during joint movement.
margins of articular cartilages in a transitional zone that occupies the Subintimal adipose cells form compact lobules surrounded by highly
peripheral few millimetres of cartilage. Synovial membrane secretes and vascular fibro elastic interlobular septa that provide firmness and com
absorbs a fluid that lubricates the movement between the articulating pressive turgor.
surfaces. The intimal layer consists of pleomorphic synovial cells embedded
Pink, smooth and shining, the internal synovial surface displays a in a granular, amorphous matrix. In normal human joints, synovial cells
few small synovial villi that increase in size and number with age. Folds form an interlacing, discontinuous layer, 1–3 cells and 20–40 µm thick,
and fringes of membrane may also project into a joint cavity; some are between the subintima and the joint cavity. They are not separated from


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the subintima by a basal lamina, and are distinguished from subintimal of articular margins; facilitation of rolling movements; and spread of
cells only because they associate to form a superficial layer. In many lubricant. The temporomandibular disc has attracted particular atten
locations, but particularly over loose subintimal tissue, areas are com tion because of its exceptional, perhaps unique, design and biome
monly found that are free from synovial cells. Over fibrous subintimal chanical properties.
tissue the synovial cells may be flattened and closely packed, forming The functions of labra and fat pads, two other quite common types
endotheliumlike sheets. Human synovial cells are generally elliptical, of intraarticular structure, are also uncertain. A labrum is a fibrocarti
with numerous cytoplasmic processes. Neighbouring cells are often laginous anular lip, usually triangular in crosssection, attached to an
separated by gaps, but their processes may interdigitate where they lie articular margin such as the glenoid fossa or acetabulum. It deepens
closer together. There is considerable regional variation in cell morphol the socket and increases the area of contact between articulating sur
ogy and numbers. faces, and may act as a lubricant spreader. Like menisci, labra may
There are at least two morphologically distinct populations of syno reduce the synovial space to capillary dimensions, thus limiting drag.
vial cells or synoviocytes: type A and type B. Type A synoviocytes are Unlike menisci, labra are not compressed between articular surfaces.
macrophagelike cells characterized by surface ruffles or lamellipodia, Small fibrous labra have been described along the ventral or dorsal
plasma membrane invaginations and associated pinocytotic vesicles, a margins of the zygapophysial joints at lumbar levels, as have meniscus
prominent Golgi apparatus but little rough endoplasmic reticulum. shaped fibroadipose meniscoids at the superior or inferior poles of the
They probably synthesize and release lytic enzymes and phagocytose same joints. Fat pads are soft and change shape to fill joint recesses that


joint debris from synovial fluid. Type B synoviocytes, which predomi vary in dimension according to joint position.
nate, resemble fibroblasts and have abundant rough endoplasmic
reticulum but fewer vacuoles and vesicles, and a less ruffled plasma Vascular supply and lymphatic drainage
membrane than type A synoviocytes. They probably synthesize some of
the hyaluronan of synovial fluid, the boundary lubricant lubricin, and
Numerous branches from periarticular arterial plexuses pierce the
inhibitors of the degradative enzymes synthesized by type A cells, limit
fibrous capsules to form subsynovial vascular plexuses. Some synovial
ing their potential to damage joint tissues. Synoviocytes do not divide
vessels end near articular margins in an anastomotic fringe, the circulus
actively in normal synovial membranes, but may do so in response to
articularis vasculosus. A lymphatic plexus in the synovial subintima
trauma and haemarthrosis. Under such conditions, type B synoviocytes
drains along blood vessels to the regional deep lymph nodes.
divide in situ, while type A cells increase by immigration of bone
Articular cartilage, intraarticular menisci and cartilaginous discs are
marrowderived precursors.
all avascular, presumably because high mechanical pressures in these
deformable tissues would collapse any blood vessels inside them. Labo
Synovial fluid
ratory experiments show that proteoglycans inhibit vascular growth, so
the high concentration of proteoglycans in the cartilaginous tissues of
Synovial fluid occupies synovial joints, bursae and tendon sheaths. In joints may help to exclude blood vessels. However, injury and disease
synovial joints it is clear or pale yellow, viscous and slightly alkaline at can alter both the mechanical and chemical environment within carti
rest (the pH lowers during activity), and contains a small mixed popula lage (Adams 2013), allowing revascularization in peripheral and dis
tion of cells and metachromatic amorphous particles. Fluid volume is rupted regions. The blood supply to subchondral bone is described on
low: usually less than 0.5 ml can be aspirated from a large joint such page 89.
as the knee.


The composition of synovial fluid is consistent with it being mainly
Innervation
a transudate of blood plasma: it contains protein (approximately
0.9 mg/100 ml) derived from the blood. It also contains hyaluronan,
which is thought to be a significant determinant of the viscoelastic and A movable joint is innervated by articular branches of the nerves that
thixotropic (flow ratedependent) properties of synovial fluid. A small supply the muscles acting on the joint and that also supply the skin
proportion (approximately 2%) of synovial fluid protein differs from covering the joint (Hilton’s law). Although there is overlap between the
plasma protein and is probably produced by type B synoviocytes. An territories of different nerves, each nerve innervates a specific part of the
even smaller proportion (approximately 0.5%) of synovial fluid protein capsule. The region made taut by muscular contraction is usually inner
appears to be a specialized lubricating glycoprotein, lubricin. Synovial vated by nerves that supply the antagonists. For example, during abduc
fluid contains a few cells (approximately 60 per ml in resting human tion, stretching the portion of the capsule of the hip joint supplied by
joints), including monocytes, lymphocytes, macrophages, synovial the obturator nerve elicits reflex contraction of the adductors that is
intimal cells and polymorphonuclear leukocytes; higher counts are usually sufficient to prevent damage.
found in young individuals. The amorphous metachromatic particles Myelinated axons in articular nerves innervate Ruffini endings,
and fragments of cells and fibrous tissue found in synovial fluid are lamellated articular corpuscles, and structures resembling Golgi tendon
presumed to be the byproducts of wear and tear. organs. Ruffini endings respond to stretch and adapt slowly, whereas
lamellated corpuscles respond to rapid movement and vibration, and
adapt rapidly; both types of receptor register the speed and direction of
Intra-articular menisci, discs and fat pads
movement. Golgi tendon organs, innervated by the largest myelinated
axons (10–15 µm diameter), are slow to adapt; they mediate position


An articular disc or meniscus can occur between articular surfaces where sense and also are concerned in stereognosis, i.e. recognition of shape
congruity (conformity of opposing articular surfaces) is low. The term of held objects. Simple endings are numerous at the attachments of
meniscus should be reserved for incomplete discs, like those in the knee capsules and ligaments, and are thought to be the terminals of unmy
joint and, occasionally, in the acromioclavicular joint. Complete discs, elinated and thinly myelinated nociceptive axons (see p. 59 for an
such as those in the sternoclavicular and inferior radioulnar joints, account of sensory receptors).
extend across a synovial joint, thereby dividing it structurally into two Many unmyelinated postganglionic sympathetic axons terminate
synovial cavities; they often have small perforations. The disc in the near vascular smooth muscle, and are presumably either vasomotor or
temporomandibular joint may be complete or incomplete. vasosensory. The nerve endings in synovial membrane are believed to
The main part of a disc is relatively acellular, but the surface may be supply blood vessels exclusively, from which it is assumed that synovial
covered by an incomplete stratum of flat cells, continuous at the periph membrane is normally relatively insensitive to pain.
ery with adjacent synovial membrane. Discs are usually connected to Cartilaginous structures within joints normally have no nerve supply,
their fibrous capsule by vascularized connective tissue, so that they partly because they are avascular and partly because axonal growth is
become invaded by blood vessels and afferent and vasomotor post inhibited by a high concentration of proteoglycans. However, when
ganglionic sympathetic nerves. The union between disc and capsule fibrocartilage is injured or diseased, nerves may accompany the conse
may be closer and stronger, as occurs in the knee and temporoman quent ingrowth of blood vessels and give rise to pain (Freemont et al
dibular joints. Discs and menisci are composed of fibrocartilage con 1997). Subchondral bone is normally innervated and is a likely source
taining crimped type I collagen fibres, and are not covered by synovial of pain in the spine (Peng et al 2009).
membrane.


The functions of intraarticular fibrocartilages are uncertain. Evi
Classification
dence from structural or phylogenetic data, aided by mechanical analo
gies, suggests that functions include: improvement of fit between
articulating surfaces; deployment of weight over larger surface areas; Synovial joints can be classified according to their shape (Fig. 5.33).
shock absorption; facilitation of combined movements; limitation of While this has some practical value, it should be remembered that they
translational (gliding) movements at joints such as the knee; protection are merely variations, sometimes extreme, of basic forms. Articular


Joints
101
5
RETPAHC
1 Plane joint 4 Ellipsoid joint
2 Hinge joint 5 Saddle joint
3 Pivot joint 6 Ball-and-socket joint
Fig. 5.33 Types of synovial joint, with selected examples.
surfaces are never truly flat, or complete spheres, cylinders, cones or metacarpophalangeal joints. Primary movements occur around two
ellipsoids. orthogonal axes, such as flexion–extension and abduction–adduction,
and may be combined as circumduction. Rotation around the third axis
Plane joints
is largely prevented by general articular shape.
Plane joints, such as intermetatarsal and some intercarpal joints, have
Saddle joints
almost flat surfaces. Slight curvature is often disregarded, although it is
usual, and movements are considered to be pure translations or sliding Saddle joints are biaxial joints in which the articular surfaces have both
between bones. concave and convex regions. Each surface is maximally convex in one
direction and maximally concave in another, at right angles to the first.
Hinge joints The convexity of the larger surface is apposed to the concavity of the
These resemble hinges because movement takes place about a single smaller surface and vice versa. Primary movements occur in two ortho
stationary axis, and so is largely restricted to one plane. Examples are gonal planes but articular shape also causes axial rotation of the moving
interphalangeal and humeroulnar joints. However, the surfaces of bone. Such ‘coupled’ rotation is never independent, and can be func
biological hinges are not truly cylindrical, and actual motion can tionally significant in habitual positioning and limitation of move
occur in more than one plane. Hinge joints possess strong collateral ment. The most familiar saddle joint is the carpometacarpal joint of the
ligaments. thumb; other examples include the ankle and calcaneocuboid joints.
Bicondylar joints are predominantly uniaxial hinge joints, but the
Ball-and-socket joints
presence of two condyles side by side allows limited rotation about a
second axis orthogonal to the first. These joints are formed from two These multiaxial joints are formed by a globoid ‘head’ articulating with


convex condyles that articulate with concave or flat surfaces. The con an opposing cup. Prime examples are the hip and shoulder joints.
dyles may lie within a common fibrous capsule (as in the knee), or in Although their surfaces resemble parts of spheres, they are not strictly
separate capsules that necessarily cooperate in all movements as a con spherical but slightly ovoid, and consequently congruence is not perfect
dylar pair (as in the temporomandibular joints). in most positions. Indeed, it occurs in only one position, at the end of
the most common movement.
Pivot joints
These are uniaxial joints in which an osseous pivot inside an osteoliga Factors influencing movement
mentous ring allows rotation only around the axis of the pivot. Pivots
may rotate in rings (e.g. the head of the radius rotates within the anular Movements at synovial joints depend on a number of factors, including
ligament and ulnar radial notch), or rings may rotate around pivots the complexity and number of articulating surfaces, and the number
(e.g. the atlas rotates around the dens of the axis). and position of the principal axes of movement.
Ellipsoid joints Complexity of form
Ellipsoid joints are biaxial, and consist of an oval, convex surface Most synovial joints are simple articulations between two articular
apposed to an elliptical concavity. Examples are the radiocarpal and surfaces. A joint with more than two articular surfaces is called a


FunCTionAl AnATomy oF THE musCuloskElETAl sysTEm
102
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A B C Fig. 5.34 The shoulder joint is multiaxial and
possesses three degrees of freedom. The three
mutually perpendicular axes are shown, around which
the principal movements of flexion–extension (A),
abduction–adduction (B) and medial and lateral
rotation (C) occur. Note that these axes are referred to
the plane of the scapula and not to the coronal and
sagittal planes of the erect body. Although an infinite
variety of additional movements may occur at such a
joint, e.g. movements involving intermediate planes or
combinations, they can always be resolved
mathematically into components related to the three
axes illustrated.
Where movement is slight, the reciprocal surfaces are of similar size;
where it is wide, the habitually more mobile bone has the larger articu
lar surface.
r4
r3 Translation
Translation is the simplest motion and involves gliding or sliding
without appreciable angulation. Although frequently combined with
other movements, it is often considered the only motion permitted in
r2 some carpal and tarsal articulations. However, cineradiography reveals
that considerable angulation occurs during movements of the small
carpal and tarsal bones.
r1 Flexion
Flexion is an example of angulation, where there is a change in angle
Fig. 5.35 A profile of a section through an ovoid surface showing that it between the topographical axes of the articulating bones. Although a
may be considered as a series of segments of circles of changing radius. widely used term, flexion is difficult to define. It often means approxi
The radius of curvature of joint surfaces often changes from one location mation of two ventral surfaces around a transverse axis. However, the
to another. thumb is almost at right angles to the fingers: its ‘dorsal’ surface faces
laterally so that flexion and extension at its joints occur around antero
compound joint, e.g. the knee and the elbow (see Fig. 5.31). In all
posterior axes. At the shoulder, flexion is referred to an oblique axis
compound joints, articulating territories remain distinct. A synovial


through the centre of the humeral head in the plane of the scapular
joint that contains an intraarticular disc or meniscus is called a complex
body, the arm moving anteromedially forwards and hence nearer to the
joint, e.g. the tibiofemoral joint of the knee, and the temporomandibu
ventral aspect of the trunk. At the hip, which has a transverse axis,
lar joints.
flexion brings the morphologically dorsal (but topographically ventral)
Degrees of freedom surface of the thigh to the ventral aspect of the trunk. Description of
flexion at the ankle joint is complicated by the fact that the foot is set
Joint motion can be described by rotation and translation about three
at a right angle to the leg. Elevation of the foot diminishes this angle
orthogonal axes. There are three possible rotations (axial, abduction–
and is usually termed flexion; however, it involves the approximation
adduction, flexion–extension) and three possible translations (proxi
of two dorsal surfaces so might equally be called extension. Flexion has
modistal, mediolateral, anteroposterior). Each is a degree of freedom.
also been defined as the fetal posture, implying that elevation of the
For most joints, translations are small and can be neglected (Fig. 5.34).
foot is flexion, a view supported by withdrawal reflexes in which eleva
A few joints have minor but pure translatory movements, but most joint
tion is always associated with flexion at the knee and hip. Definitions
motion is by rotation.
based on morphological and physiological considerations are thus con
When movement is practically limited to rotation about one axis
tradictory; to avoid confusion, dorsiflexion and plantar flexion are used
(e.g. the elbow), a joint is termed uniaxial and has one degree of
to describe ankle movements.
freedom. If independent movements can occur around two axes (e.g.
flexion–extension and axial rotation in the knee), the joint is biaxial Abduction and adduction
and has two degrees of freedom. Since there are three axes for independ
Abduction and adduction occur around anteroposterior axes except at
ent rotation, joints may have up to three degrees of freedom. This
the first carpometacarpal and shoulder joints. The terms generally imply


apparently simple classification is complicated by the complexity of
lateral or medial angulation, except in digits, where arbitrary planes are
joint structure and has consequent effects on motion. Even though a
chosen (midlines of the middle digit of the hand and second digit of
true ‘ballandsocket’ joint is multiaxial and can rotate about many
the foot), because these are least mobile in this respect. Abduction of
chosen axes, for each position there is a maximum of three orthogonal
the thumb occurs around a transverse axis and away from the palm.
planes, which means that it can have, as a maximum, three degrees of
Similarly, abduction of the humerus on the scapula occurs in the scapu
freedom.
lar plane around an oblique axis at right angles to it.
For a uniaxial hinge joint with a single degree of freedom, a single
unchanging axis of rotation would be predicted. However, because the Axial rotation
shapes of joint surfaces are complex, there is a variable radius of curva
Axial rotation is a widely, but often imprecisely, used term. Its restricted
ture (Fig. 5.35) and consequently the axis of rotation will vary as joint
sense denotes movement around some notional ‘longitudinal’ axis,
movement progresses. When the variation is minor, e.g. in the elbow,
which may even be in a separate bone, e.g. the dens of the second cervi
it is often appropriate to describe a mean position for the axis, whereas
cal vertebra, on which the atlas rotates. An axis may approximate to the
in other joints, e.g. the knee, the situation is more complex.
centre of the shaft of a long bone, as in medial and lateral humeral
Motion in one direction is often linked to motion in another.
rotation (see Fig. 5.34). Alternatively, the axis may be at an angle to the
Coupled (or conjunct) movements occur as an integral and inevitable
topographical axis of a bone, as in movement of the radius on the ulna
accompaniment of the main movement. Adjunct movements can
in pronation and supination, where the axis joins the centre of the
occur independently and may or may not accompany the principal
radial head to the base of the ulnar styloid process. In these examples,
movement.


rotations can be independent adjunct motions, constituting a degree of
freedom, or obligatory (coupled) rotations, which always accompany
Types of joint movement
some other main movement as a consequence of articular geometry.
Obligatory coupled motion is frequently combined with a degree of
Joint surfaces move by translation (gliding) and angulation (rotation), voluntary adjunct motion, the latter dictating what proportion of the
usually in combination, to produce gross movements at the joint. motion occurs above the minimum obligatory component.


skeletal muscle
103
5
RETPAHC
Circumduction
Circumduction combines successive flexion, abduction, extension and
adduction, and occurs when the distal end of a long bone circumscribes
the base of a cone that has its apex at the joint in question. Examples
are circular movements of the hand and foot about the shoulder and
hip joints, respectively.
DEVELOPMENT OF JOINTS
The development of joints is described in the context of limb develop NN
ment on page 222.
MUSCLE
CC
Most cells possess cytoskeletal elements that are capable of lengthen
ing or shortening and so enable the cell to change its shape. This
capacity is important in a variety of cellular functions, including loco
motion, phagocytosis and mitosis. Slow movements can be effected by Fig. 5.36 Skeletal muscle fibres from human lateral rectus in longitudinal
polymerization–depolymerization mechanisms involving actin and section, showing transverse striations representing the sarcomeric
tubulin, but much faster and more forceful movements can be created organization of actin and myosin filaments. The variation in fibre diameter
by the socalled ‘motor proteins’, which use energy from the hydrolysis is typical of extraocular muscles. Capillaries (C) and nerves (N) lie
of adenosine 5′triphosphate (ATP). Of these ATPdependent systems, between the fibres, orientated mainly in parallel and so are also sectioned
longitudinally. Toluidine blue stained resin section. (Provided by courtesy
one of the most widespread is based on the interaction of the motor
of the Department of Optometry and Visual Science, City University,
protein myosin with actin.
London.)
In muscle cells the filaments of actin, myosin and other associated
proteins are so abundant that they almost fill the interior of the cell.
Moreover, they align predominantly in one direction, so that interac
tions at the molecular level are translated into linear contraction of the Individual fibres are long, cylindrical structures that tend to be consist
whole cell. The ability of these specialized cells to change shape has ent in size within a given muscle, but in different muscles may range
thus become their most important property. Assemblies of contractile from 10 to 100 µm in diameter, and from a few millimetres to many


muscle cells, the muscles, are machines for converting chemical energy centimetres in length. The cytoplasm of each fibre, the sarcoplasm, is
into mechanical work. Muscle forces move limbs and drive many of the surrounded by a plasma membrane often called the sarcolemma. The
functions of the human body, and muscle tissue constitutes 40–50% of bulk of the sarcoplasm comprises the contractile machinery, organized
body mass. into myofibrils (see Fig. 5.37) 1–2 µm in diameter, which extend the
length of the fibre. Numerous moderately euchromatic, oval nuclei
usually occupy a thin transparent rim of sarcoplasm between the myofi
CLASSIFICATION OF MUSCLE
brils and the sarcolemma, and are especially numerous in the region of
the neuromuscular junction (see Fig. 3.34). In transverse section, a
Muscle cells (fibres) are also known as myocytes (the prefixes myo and muscle fibre may reveal only one or two nuclei, but it may contain
sarco are frequently used in naming structures associated with muscle). several hundred along its entire length. Myogenic satellite cells lie
They differentiate along one of three main pathways to form skeletal, between the sarcolemma and the surrounding basal lamina (see below).
cardiac or smooth muscle. Both skeletal and cardiac muscle (Ch. 6) may
be called striated muscle, because their myosin and actin filaments are Sarcomeres
organized into regular, repeating structures (sarcomeres), which give the
cells a finely crossstriated appearance when viewed microscopically.
Although myofibrils are too tightly packed to be visible by routine light
Cardiac muscle fibres are relatively short, with branched ends, and are
microscopy, their presence can be inferred from transverse striations
joined to adjacent fibres at intercellular junctional complexes called
across the tissue. Crossstriations may be demonstrated more effectively
intercalated discs, which skeletal muscle lacks. Smooth muscle cells
using special stains (see Fig. 5.36) or under polarized light, which can
lack striations because their actin and myosin are not organized into
differentiate dark, anisotropic Abands (which are birefringent and
sarcomeres.
rotate the plane of polarized light strongly) from lighter, isotropic


Other contractile cells, including myofibroblasts and myoepithelial
Ibands (rotate the plane of polarized light to a negligible degree). In
cells, are different in character and developmental origin. They contain
transverse section, skeletal muscle fibres are usually polygonal (Fig.
smooth musclelike contractile proteins and are found singly or in
5.38) and their sarcoplasm often has a stippled appearance, because
small groups.
transversely sectioned myofibrils are resolved as dots. The packing
density of muscle fibres varies, from low (in the extrinsic muscles of the
SKELETAL MUSCLE larynx) to high (in the group of muscles that elevate the mandible).
Most detail is revealed by transmission electron microscopy (Fig.
5.39). Myofibrils, approximately 1 µm in diameter, are the dominant
Skeletal muscle (striated, voluntary) is the most common muscle tissue.
ultrastructural feature. In longitudinal sections they appear as ribbons
It consists of long, parallel multinucleate cells bundled together by col
that are interrupted at regular intervals by thin dark transverse lines,
lagenous sheaths. Its regular organization enables skeletal muscle to
which correspond to discs in the parent cylindrical structure. These are
generate powerful contractions, with a power output of approximately
the Zlines or, more properly, Zdiscs (Zwischenscheiben = interval
100 watts per kilogram of tissue. However, the price paid for this organi
discs) that divide each myofibril into a linear series of repeating con
zation is a limited contractile range: skeletal muscle can shorten by only
tractile units, the sarcomeres. A sarcomere is typically 2.2 µm long in
30%. If a larger range of movement is required, it must be achieved
resting muscle. At higher power, it can be seen to consist of two types
through the amplification provided by lever systems, as described in
of filament, thick and thin, organized into regular arrays (see Figs 5.37
Figure 5.63. Skeletal muscle is innervated by somatic motor nerves and
and 5.39). Thick filaments, which are approximately 15 nm in diame
is sometimes referred to as voluntary muscle, because its contractions


ter, are composed mainly of myosin. Thin filaments, which are 8 nm
are often initiated under conscious control. However, this is a mislead
in diameter, are composed mainly of actin. The arrays of thick and thin
ing term because skeletal muscle is involved in many movements, such
filaments form a partially overlapping structure in which electron
as breathing, blinking and swallowing, which are often initiated at an
density (as seen in the electron microscope) varies according to the
unconscious level.
amount of protein present. The Aband consists of the thick filaments,
together with lengths of thin filaments that interdigitate with, and thus
MICROSTRUCTURE OF SKELETAL MUSCLE overlap, the thick filaments at either end (see Fig. 5.39; Fig. 5.40). The
central, paler region of the Aband, which is not penetrated by the thin
Skeletal muscle fibres are enormous multinucleate cells (Figs 5.36– filaments, is called the Hzone (Helle = light). At their centres, the thick
5.37), which develop by fusion of individual myoblasts (see below). filaments are linked together transversely by material that constitutes


Functional anatomy of the musculoskeletal system
103.e1
5
RETPAHC
Titin Nebulin Myosin Actin
B Z M Z
Fig. 5.40 B, The arrangement of titin and nebulin in a skeletal muscle sarcomere. A single titin molecule spans from the Z-disc to the M-band and
contains a spring-like ‘elastic’ region that develops force when the sarcomere is stretched. Nebulin extends from the Z disc for the full length of each
actin filament. (From Prado LG et al. Isoform Diversity of Giant Proteins in Relation to Passive and Active Contractile Properties of Rabbit Skeletal
Muscles. J Gen Physiol 2005;126:461–480.)


FunCTionAl AnATomy oF THE musCuloskElETAl sysTEm
104
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Thin filaments
Thick filaments
Myofilaments
Fig. 5.38 A transverse cryostat section of adult human skeletal muscle.
Note the tight packing of the fibres and the peripheral location of the
dark-stained nuclei. (Photograph by Professor Stanley Salmons, from a
specimen provided by courtesy of Tim Helliwell, Department of Pathology,
University of Liverpool.)
Sarcomere The high degree of organization of thick and thin filaments is equally
evident in transverse sections (see Fig. 5.40; Fig. 5.41). The thick myosin
Myofibril filaments form a hexagonal lattice. In the regions where they overlap
the thin filaments, each myosin filament is surrounded by six actin fila
Fibres Nerve
ments at the trigonal points of the lattice. In the Iband, the thin fila
ment pattern changes from hexagonal to square as the filaments
approach the Zdisc, where they are incorporated into a square lattice
structure.
The banded appearance of individual myofibrils is a function of the
regular alternation of the thick and thin filament arrays. The size of
Mitochondrion
myofibrils places them at the limit of resolution of light microscopy;
crossstriations are only visible at that level because of the alignment
in register of the A and Ibands in adjacent myofibrils across the width
of the whole muscle fibre. In suitably stained relaxed material, the A,
I and Hbands are quite distinct, whereas the Zdiscs, which are such
a prominent feature of electron micrographs, are thin and much less
conspicuous in the light microscope, and Mlines cannot be resolved.
Muscle proteins
Myosin, the protein of the thick filament, constitutes 60% of the total
myofibrillar protein and is the most abundant contractile protein. The
thick filaments of skeletal and cardiac muscle are 1.5 µm long. Their
composition from myosin heavy and light chain assemblies is de
scribed on page 12. The other components of myosin, the regulatory
proteins tropomyosin and troponin, play a major part in the control of
contraction.


Actin is the next most abundant contractile protein and constitutes
20% of the total myofibrillar protein. In its filamentous form, Factin,
Fasciculi
it is the principal protein of the thin filaments. A number of congenital
myopathies result from gene mutations in components of the thin fila
ment assembly (Clarkson et al 2004).
A third type of long sarcomeric filament (not shown in Fig. 5.40)
connects the thick filaments to the Zdisc, and is formed by the giant
protein, titin, which has a molecular mass in the millions (Gregorio
et al 1999). Single titin molecules span the halfsarcomere between the
Mlines and the Zdiscs, into which they are inserted. They have a teth
ered portion in the Aband, where they are attached to thick filaments
as far as the Mline, and an elastic portion in the Iband. The elastic
properties of titin endow the relaxed muscle fibre with passive resist
ance to stretching, and with elastic recoil.
A number of proteins that are neither contractile nor regulatory are
responsible for the structural integrity of the myofibrils, particularly
their regular internal arrangement. A component of the Zdisc, αactinin,
is a rodshaped molecule that anchors the plusends of actin filaments
Fig. 5.37 Levels of organization within a skeletal muscle, from whole from adjacent sarcomeres to the Zdisc. Nebulin inserts into the Zdisc,
muscle to fasciculi, single fibres, myofibrils and myofilaments. associated with the thin filaments, and regulates the lengths of actin
filaments. Desmin, an intermediate filament protein characteristic of
muscle, encircles the myofibrils at the Zdisc and, with the linking
the Mline (Mittelscheibe = middle [of] disc), which is visible in most molecule plectrin, forms a meshwork that connects myofibrils together
muscles. The Iband consists of the adjacent portions of two neighbour within the muscle fibre and to the sarcolemma. Myomesin holds
ing sarcomeres in which the thin filaments are not overlapped by thick myosin filaments in their regular lattice arrangement in the region of


filaments. The thin filaments of adjacent sarcomeres are anchored in the Mline. Dystrophin is confined to the periphery of the muscle fibre,
the Zdisc, which bisects the Iband. close to the cytoplasmic face of the sarcolemma. It binds to actin


skeletal muscle
105
5
RETPAHC
Fig. 5.39 The electron microscopic appearance
M
of skeletal muscle in longitudinal section. A, A
low-power view of parts of two adjacent muscle
M
fibres, separated by endomysium (E) containing
capillaries (C) and a peripherally placed nucleus
(N) in the fibre. Mitochondria (arrows) are situated
peripherally and between myofibrils (M). Myofibrils
pack the cytoplasm, with their sarcomeres
(contractile units) in register, as seen by the
C alignment of Z-discs (dark transverse lines) across
each muscle fibre. B, A sarcomere within a
myofibril, and parts of two others. (A sarcomere is
the distance between adjacent Z-discs.) Also seen
E are the A-band, bisected by the M-line, and
I-band, which here is almost obliterated in the
contracted state (see Fig. 5.40). A triad is visible
between myofibrils, comprised of a T-tubule (long
arrow) and two terminal cisternae of sarcoplasmic
reticulum (short arrows). (A, Provided courtesy of
Professor Hans Hoppeler, Institute of Anatomy,
NN University of Bern, Switzerland.)
M
Z
A
I
One
sarcomere
A B
Pseudo
H zone
Z M I
H
A
Relaxed
1 µm Sarcomere Contracted
A
Fig. 5.40 A, Sarcomeric structures. The drawings below the electron micrograph (of two myofibrils sectioned longitudinally and with their long axes
orientated transversely) indicate the corresponding arrangements of thick and thin filaments. Relaxed and contracted states are shown to illustrate the
changes that occur during shortening. Insets at the top depict the electron micrographic appearance of transverse sections through the myofibril at the
levels shown. Note that the packing geometry of the thin filaments changes from a square array at the Z-disc to a hexagonal array where they
interdigitate with thick filaments in the A-band. (Photographs by Professor Brenda Russell, Department of Physiology and Biophysics, University of Illinois
at Chicago.) (B, continued online)


intracellularly and is also associated with a large oligomeric complex with a reduced size and/or abundance of dystrophin. Female carriers
of glycoproteins, the dystroglycan/sarcoglycan complex that spans the (heterozygous for the mutant gene) of Duchenne muscular dystrophy
membrane and links specifically with merosin, the αlaminin isoform may also have mild symptoms of muscle weakness. At about 2500 kb,
2
of the muscle basal lamina. This stabilizes the muscle fibre and trans the gene is one of the largest yet discovered, which may account for the
mits forces generated internally on contraction to the extracellular high mutation rate of Duchenne muscular dystrophy (approximately
matrix. 35% of cases are new mutations). Other muscular dystrophies may
Dystrophin is the product of the gene affected in Duchenne muscu involve deficiencies in proteins functionally associated with dystrophin,
lar dystrophy, a fatal disorder that develops when mutation of the gene such as the dystroglycan/sarcoglycan complex or αlaminin; they may
2
leads to the absence of the protein (Batchelor and Winder 2006). A also be the result of mutations in proteins of the inner nuclear mem
milder form of the disease, Becker muscular dystrophy, is associated brane (Azibani et al 2014; Koch and Holaska 2014).


FunCTionAl AnATomy oF THE musCuloskElETAl sysTEm
106
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noiTCEs
Fig. 5.41 An electron micrograph of skeletal
muscle in transverse section, showing parts of two
muscle fibres. Part of a capillary (C) is seen in
transverse section in the endomysial space. The
variation in the appearance of myofibrils in
cross-section is explained in Figure 5.40.
(Photograph by Professor Brenda Russell,
Department of Physiology and Biophysics,
University of Illinois at Chicago.)
C
Other sarcoplasmic structures Mitochondria
Myofibrils
Although myofibrils are the dominant ultrastructural feature, skeletal
muscle fibres contain other organelles essential for cellular function.
Ribosomes, Golgi apparatus and mitochondria are located around the
nuclei, between myofibrils and the sarcolemma, and, to a lesser extent,
between the myofibrils. Mitochondria, lipid droplets and glycogen
provide the metabolic support needed by active muscle. The mitochon
dria are elongated and their cristae are closely packed. The number of Triad
mitochondria in an adult muscle fibre is not fixed, but can increase or
decrease quite readily in response to sustained changes in activity.
Spherical lipid droplets, approximately 0.25 µm in diameter, are dis I-band Actin
tributed uniformly throughout the sarcoplasm between myofibrils. T-tubule
They represent a rich source of energy that can be tapped only by oxida
tive metabolic pathways; they are therefore more common in fibres that
have a high mitochondrial content and good capillary blood supply. Myosin
Small clusters of glycogen granules are dispersed between myofibrils A-band Sarcoplasmic
and among the thin filaments. During brief bursts of activity, they reticulum
provide an important source of anaerobic energy that is not dependent
on blood flow to the muscle fibre.
Tubular invaginations of the sarcolemma penetrate between the Z-disc
myofibrils in a transverse plane at the limit of each Aband (see Fig. T-tubule
5.39; Fig. 5.42). The lumina of these transverse (T)tubules are thus


in continuity with the extracellular space. At the ends of the muscle
fibre, where force is transmitted to adjacent connective tissue struc
tures, the sarcolemma is folded into numerous fingerlike projec
tions that strengthen the junctional region by increasing the area of
Basal lamina
attachment.
The sarcoplasmic reticulum (SR) is a specialized form of smooth
endoplasmic reticulum and forms a plexus of anastomosing membrane
T-tubules
cisternae that fills much of the space between myofibrils (see Fig. 5.42).
The cisternae expand into larger sacs, junctional sarcoplasmic reticulum
Sarcolemma
or terminal cisternae, where they come into close contact with Ttubules,
forming structures called triads (see Figs 5.39 and 5.42). The mem
branes of the SR contain calcium–ATPase pumps that transport calcium
ions into the terminal cisternae, where the ions are bound to calseques
trin, a protein with a high affinity for calcium, in dense storage granules.
In this way, calcium can be accumulated and retained in the terminal
cisternae at a much higher concentration than elsewhere in the sarco Fig. 5.42 A three-dimensional reconstruction of a mammalian skeletal
plasm. Ca2+release channels (ryanodine receptors) are concentrated muscle fibre, showing in particular the organization of the transverse (T)
mainly in the terminal cisternae and form one half of the junctional tubules and sarcoplasmic reticulum. Mitochondria lie between the
‘feet’ or ‘pillars’ that bridge the SR and Ttubules at the triads. The other myofibrils. Note that transverse tubules are found at the level of the A/I
half of the junctional feet is the Ttubule receptor that constitutes the junctions, where they form triads with the terminal cisternae of the
voltage sensor. sarcoplasmic reticulum.


skeletal muscle
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Connective tissues of muscle muscles possess a single vascular pedicle supplying the muscle belly,
e.g. tensor fasciae latae (supplied by the ascending branch of the lateral
circumflex femoral artery) and gastrocnemius (supplied by the sural
The endomysium is a delicate network of connective tissue that sur
artery). Type II muscles are served by a single dominant vascular pedicle
rounds muscle fibres and forms their immediate external environment.
and several minor pedicles, and can be supported on a minor pedicle
It is the site of metabolic exchange between muscle and blood, and
as well as the dominant pedicle, e.g. gracilis (supplied by the medial
contains capillaries and bundles of small nerve fibres. Ion fluxes associ
circumflex femoral artery in the dominant pedicle). Type III muscles are
ated with the electrical excitation of muscle fibres take place through
supplied by two separate dominant pedicles, each from different source
its proteoglycan matrix. The perimysium is a more substantial connec
arteries, e.g. rectus abdominis (supplied by the superior and inferior
tive tissue structure that is continuous with the endomysium, and
epigastric arteries) and gluteus maximus (supplied by the superior and
ensheathes groups of muscle fibres to form parallel bundles, or fas
inferior gluteal arteries). Type IV muscles have multiple small pedicles
ciculi. It carries larger blood vessels and nerves, and accommodates
that, in isolation, are not capable of supporting the whole muscle, e.g.
neuromuscular spindles. Perimysial septa are themselves the inward
sartorius and tibialis anterior; about 30% survive reduction on to a
extensions of a collagenous sheath, the epimysium, which forms part
single vascular pedicle. Type V muscles have one dominant vascular
of the fascia that invests whole muscle groups.
pedicle and multiple secondary segmental pedicles, e.g. latissimus dorsi
Epimysium consists mainly of type I collagen; perimysium contains
(supplied by the thoracodorsal artery as the primary pedicle, thoraco
type I and type III collagen; endomysium contains collagen types III


lumbar perforators from the lower six intercostal arteries and the
and IV. Collagen IV is associated particularly with the basal lamina that
lumbar arteries as the segmental supply) and pectoralis major (supplied
invests each muscle fibre. The epimysial, perimysial and endomysial
by the pectoral branch of the thoracoacromial axis as the dominant
sheaths coalesce where the muscles connect to adjacent structures at
pedicle, and anterior perforators from the internal thoracic vessels as
tendons, aponeuroses and fasciae (see below).
the segmental supply).
In crosssections of muscle, the number of capillary profiles found
NEUROVASCULAR SUPPLY OF MUSCLE adjacent to fibres usually varies from 0 to 3. Muscle fibres involved in
sustained activities, such as posture, are served by a denser capillary
Vascular supply and lymphatic drainage network than fibres that are recruited only infrequently. It is common
for muscles to receive their arterial supply via more than one route. The
accessory arteries penetrate the muscle at places other than the hilum,
In most muscles, the major source artery enters on the deep surface,
and ramify in the same way as the principal artery, forming vascular
frequently in close association with the principal vein and nerve,
territories. The boundaries of adjacent territories are spanned by anas
forming a neurovascular hilum. The vessels subsequently course and
tomotic vessels, sometimes at constant calibre, but more commonly
branch within the connective tissue framework of the muscle. Smaller
through reducedcalibre arteries or arterioles that are referred to as
arteries and arterioles ramify in the perimysial septa and give off capil
‘choke vessels’. These arterial arcades link the territories into a continu
laries that run in the endomysium. The smaller vessels lie mainly paral
ous network.
lel to the muscle fibres, but also branch and anastomose around the
Veins branch in a similar way, forming venous territories that cor
fibres, forming an elongated mesh.
respond closely to the arterial territories. In the zones where the arterial
The gross vascular anatomy of muscles has been classified into five
territories are linked by choke vessels, the venous territories are linked
types according to the number and relative dominance of vascular


by anastomosing veins: in this case, without change of calibre. On either
pedicles that enter the muscle (Mathes and Nahai 1981) (Fig. 5.43).
side of these venous bridges, the valves in the adjacent territories direct
This classification has important surgical relevance in determining
flow in opposite directions towards their respective pedicles, but the
which muscles will survive, and therefore be useful for pedicled or free
connecting veins themselves lack valves and therefore permit flow in
tissue transfer procedures in plastic and reconstructive surgery. Type I
either direction.
Because of the potential for relative movement within muscle
groups, vessels tend not to cross between muscles, but radiate to them
Type I Type II Type III Type IV
from more stable sites or cross at points of fusion. Where a muscle
underlies the skin, blood vessels bridge between the two. These may be
primarily cutaneous vessels, which supply the skin directly but contrib
ute small branches to the muscle as they pass through it, or they may
be the terminal branches of intramuscular vessels, which leave the
muscle to supplement the cutaneous blood supply. The latter are less
frequent where the muscle is mobile under the deep fascia. Correspond
ence between the vascular territories in the skin and underlying tissues
gave rise to the concept of angiosomes, which are composite blocks of
tissue supplied by named distributing arteries and drained by their
Gluteus maximus companion veins (see Taylor and Pan (1998) for further analyses of
muscle angiosomes).
Pressure exerted on valved intramuscular veins during muscle con
traction functions as a ‘muscle pump’ that promotes venous return to
the heart. In some cases this role appears to be amplified by veins that
pass through the muscle after originating elsewhere in superficial or
Sartorius deep tissues. The extent to which the muscle capillary bed is perfused
can be varied in accordance with functional demand. Arteriovenous
anastomoses, through which blood can be returned directly to the
Type V
venous system without traversing the capillaries, provide an alternative,
Tensor Gracilis
fasciae latae regulated pathway.
The lymphatic drainage of muscles begins as lymphatic capillaries
in epimysial and perimysial, but not endomysial, sheaths. These con


verge to form larger lymphatic vessels that accompany the veins and
drain to the regional lymph nodes.
Innervation
Every skeletal muscle is supplied by one or more nerves. Muscles in the
limbs, face and neck are usually innervated by a single nerve, even
though the axons it contains may be derived from neurones located in
Latissimus dorsi several spinal cord segments and their associated ganglia. Muscles such
Fig. 5.43 Classification of muscles according to their blood supply. (With as those of the abdominal wall, which originate from several embryonic
permission from Cormack GC, Lamberty BGH 1994 The Arterial Anatomy segments, are supplied by more than one nerve. In most cases, the nerve
of Skin Flaps, 2nd edn. Edinburgh: Churchill Livingstone.) travels with the principal blood vessels within a neurovascular bundle


FunCTionAl AnATomy oF THE musCuloskElETAl sysTEm
108
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noiTCEs
(see Fig. 2.9), approaches the muscle near to its least mobile attach all parts of the muscle fibre are activated rapidly and almost synchro
ment, and enters the deep surface at a position that is more or less nously. Excitation–contraction coupling is the process whereby an
constant for each muscle. action potential triggers the release of calcium from the terminal cister
Nerves supplying muscle are frequently referred to as ‘motor nerves’ nae of the sarcoplasmic reticulum into the cytosol. This activates a
but they contain both motor and sensory components. The motor calciumsensitive switch in the thin filaments and so initiates contrac
component is mainly composed of large, myelinated αefferent axons, tion. At the end of excitation, the Ttubular membrane repolarizes,
which supply the muscle fibres, supplemented by small, thinly myeli calcium release ceases, calcium ions are actively transported back to the
nated γefferents, or fusimotor fibres, which innervate the intrafusal calsequestrin stores in the sarcoplasmic reticulum by the calcium–
muscle fibres of neuromuscular spindles (see p. 60), and fine, unmyeli ATPase pumps, and the muscle relaxes.
nated autonomic efferents, which innervate vascular smooth muscle. The lengths of the thick and thin filaments do not change during
The sensory component consists of large, myelinated IA and smaller muscle contraction. The sarcomere shortens by the sliding of thick and
group II afferents from the neuromuscular spindles, large myelinated thin filaments past one another, which draws the Zdiscs towards the
IB afferents from the Golgi tendon organs (see p. 59), and fine myeli middle of each sarcomere (see Fig. 5.40). As the overlap increases,
nated and unmyelinated axons that convey pain and other sensations the I and Hbands narrow to nearextinction, while the width of the
from free terminals in the connective tissue sheaths of the muscle. Abands remains constant. Filament sliding depends on the making and


Within muscles, nerves travel through the epimysial and perimysial breaking of bonds (crossbridge cycling) between myosin head regions
septa before entering the fine endomysial tissue around muscle fibres. and actin filaments. Myosin heads ‘walk’ or ‘row’ along actin filaments
Alphamotor axons branch repeatedly before they lose their myelinated using a series of short power strokes, each resulting in a relative move
sheaths to terminate in a narrow zone towards the centre of the muscle ment of 5–10 nm. Actin filament binding sites for myosin are revealed
belly, known as the motor point. Clinically, this is the place on a muscle only by the presence of calcium, which is released into the sarcoplasm
from which it is easiest to elicit a contraction with stimulating elec from the sarcoplasmic reticulum, causing a repositioning of the
trodes. Long muscles generally have two or more terminal (endplate) troponin–tropomyosin complex on actin: this is the calciumsensitive
bands because many muscle fibres do not run the full length of an switch. Myosin head binding and release are both energydependent
anatomical muscle. The terminal branch of an αmotor axon contacts and require ATP. In the absence of ATP (as occurs post mortem) the
a muscle fibre at a specialized synapse, the neuromuscular junction (see bound state is maintained, and is responsible for the muscle stiffness
Fig. 3.34). It gives off several short, tortuous branches, each ending in known as rigor mortis.
an elliptical area, the motor endplate. The underlying discoidal patch The summation of myosin power strokes leads to an average sarco
of sarcolemma, the sole plate or subneural apparatus, is thrown into mere shortening of up to 1 µm; an anatomical muscle shortens by a
deep synaptic folds. This discrete type of neuromuscular junction (en centimetre or more, depending on the muscle, because each muscle has
plaque ending) is found on muscle fibres that are capable of propagating thousands of sarcomeres in series along its length.
action potentials. A different type of ending is found on slow tonic
muscle fibres that do not have this capability, e.g. in the extrinsic ocular


Slow-twitch versus fast-twitch fibres
muscles, where slow tonic fibres form a minor component of the ana
tomical muscle. In this case the propagation of excitation is taken over
by the nerve terminals, which branch over an extended distance to form The passage of a single action potential through a motor unit elicits a
a number of small neuromuscular junctions (en grappe endings). Some twitch contraction where peak force is reached within 25–100 ms,
muscle fibres of this type receive the terminal branches of more than depending on the motor unit type involved. However, the motor
one motor neurone. The terminals of the γefferents that innervate the neurone can deliver a second nervous impulse in less time than it takes
intrafusal muscle fibres of the neuromuscular spindle also take a variety for the muscle fibres to relax. When this happens, the muscle fibres
of different forms. contract again, building the tension to a higher level. Because of this
The terminal branches of αmotor axons are normally in a ‘oneto mechanical summation, a sequence of impulses can evoke a larger force
one’ relationship with their muscle fibres: a muscle fibre receives only than a single impulse and, within certain limits, the higher the impulse
one branch, and any one branch innervates only one muscle fibre. frequency, the more force is produced (‘rate recruitment’). An alterna
When a motor neurone is excited, an action potential is propagated tive strategy is to recruit more motor units. In practice, the two mecha
along the axon and all of its branches to all of the muscle fibres that it nisms appear to operate in parallel, but their relative importance may
supplies. The motor neurone and the muscle fibres that it innervates depend on the size and/or function of the muscle; in large muscles with
can therefore be regarded as a functional unit: the ‘motor unit’. This many motor units, motor unit recruitment is probably the more impor
arrangement accounts for the more or less simultaneous contraction of tant mechanism.
a number of fibres within the muscle. The size of a motor unit varies With the exception of rare tonic fibres, skeletal muscles are com
considerably. In muscles used for precision tasks, such as the extraocular posed entirely of fibres of the twitch type. These fibres can all conduct


and intrinsic laryngeal muscles, each motor neurone innervates perhaps action potentials but they differ in other respects. Some fibres obtain
ten muscle fibres. In a large limb muscle, a motor neurone may inner their energy very efficiently by aerobic oxidation of substrates, particu
vate several hundred muscle fibres. Within a muscle, fibres belonging larly of fats and fatty acids. They have large numbers of mitochondria;
to one motor unit are distributed over a wide territory, without regard contain myoglobin, an oxygentransport pigment related to haemo
to fascicular boundaries, and they intermingle with the fibres of other globin; and are supported by a welldeveloped network of capillaries
motor units. Motor units become larger in cases of nerve damage that maintains a steady nutrient supply of oxygen and substrates. Such
because denervation induces collateral or terminal sprouting of the fibres are well suited to functions such as postural maintenance, in
remaining axons. Each new branch can reinnervate a fibre, thus increas which moderate forces need to be sustained for prolonged periods. At
ing the territory of its parent motor neurone. the other end of the spectrum, some fibres have few mitochondria, little
myoglobin and a sparse capillary network, and store energy as cytoplas
mic glycogen granules. Their immediate energy requirements are met
MUSCLE CONTRACTION largely through anaerobic glycolysis, a route that provides prompt
access to energy but that is less sustainable than oxidative metabolism.
The arrival of an action potential at the motor endplate of a neuromus They are capable of brief bursts of intense activity that must be sepa
cular junction causes acetylcholine (ACh) to be released from storage rated by extended quiescent periods during which intracellular pH and
vesicles into the highly infolded 30–50 nm synaptic cleft that separates phosphate concentrations are restored to normal values, and glycogen
the nerve ending from the sarcolemma (see Fig. 3.34). ACh is rapidly and other reserves are replenished.
bound by receptor molecules located in the junctional folds, triggering In some animals, different types of muscle fibre tend to be segregated
an almost instantaneous increase in the permeability, and hence con into different muscles. This causes some muscles to have a conspicu


ductance, of the postsynaptic membrane. This generates a local depo ously red appearance, reflecting their rich blood supply and high
larization (the endplate potential), which initiates an action potential myoglobin content associated with a predominantly aerobic metabo
in the surrounding sarcolemma. The activity of the neurotransmitter is lism, whereas other muscles have a much paler appearance, reflecting
rapidly terminated by the enzyme acetylcholinesterase (AChE), which a more anaerobic character. These variations in colour led to the early
is bound to the basal lamina in the sarcolemmal junctional folds. The classification of muscle into red and white types. This classification has
sarcolemma is an excitable membrane, and action potentials generated now been largely superseded by myosinbased typing and the presence
at the neuromuscular junction propagate rapidly over the entire surface of specific diseaserelated enzymes.
of the muscle fibre. In humans, all muscles are mixed, with fibres specialized for aerobic
Action potentials are conducted radially into the interior of the fibre working conditions intermingling with fibres of a more anaerobic or
via the Ttubules, which are extensions of the sarcolemma, ensuring that intermediate metabolic character. Different types of fibre are not readily


skeletal muscle
109
5
RETPAHC
Table 5.1 Physiological, structural and biochemical characteristics of the major The initial phase of slowing can be explained by less rapid cycling
histochemical fibre types of calcium, resulting from reduced sarcoplasmic reticulum and changes
in the amount and molecular type of proteins involved in calcium
Characteristic Fibre types
transport and binding. Chronic stimulation also triggers the synthesis
TYPE I TYPE IIA TYPE IIX of myosin heavy and light chain isoforms of the slow muscle type; the
Physiological associated changes in crossbridge kinetics result in a lower intrinsic
speed of shortening. The muscle becomes more resistant to fatigue
Function Sustained forces, Powerful, fast movements
as in posture through changes in the metabolic pathways responsible for the genera
Motor neurone firing threshold Low Intermediate High tion of ATP and a reduced dependence on anaerobic glycolysis. There
is a switch to oxidative pathways, particularly those involved in the
Motor unit size Small Large Large
breakdown of fat and fatty acids, and an associated increase in capillary
Firing pattern Tonic, Phasic, high-frequency
low-frequency density and in the fraction of the intracellular volume occupied by
mitochondria. If stimulation is discontinued, the sequence of events is
Maximum shortening velocity Slow Fast Fast
reversed and the muscle regains, over a period of weeks, all of its origi
Rate of relaxation Slow Fast Fast
nal characteristics. The reversibility of transformation is one of several
Resistance to fatigue Fatigue-resistant Fatigue-resistant Fatigue-susceptible
lines of evidence that the changes take place within existing fibres, and
Power output Low Intermediate High
not by a process of degeneration and regeneration.
Structural Many of the changes in the protein profile of a muscle that are
Capillary density High Low induced by stimulation are now known to be the result of transcrip
Mitochondrial volume High Intermediate Low tional regulation. For example, analysis of the messenger RNA species
Z-disc Broad Narrow Narrow encoding myosin heavy chain isoforms shows that expression of the
fast myosin heavy chain mRNA is downregulated within a few days of
T-tubule and sarcoplasmic Sparse Extensive
reticulum systems the onset of chronic stimulation, while the slow myosin heavy chain
mRNA is upregulated. Although myosin isoform expression is respon
Biochemical
sive to the increase in use induced by chronic stimulation, it tends to


Myosin ATPase activity Low High
be stable under physiological conditions unless these involve a sus
Oxidative metabolism High Intermediate Low
tained departure from normal postural or locomotor behaviour.
Anaerobic glycolysis Low Intermediate High
Calcium transport ATPase Low High
DEVELOPMENT AND GROWTH
OF SKELETAL MUSCLE
distinguished in routine histological preparations but are clear when Most information about the early development of the skeletal muscu
specialized enzyme histochemical techniques are used. On the basis of lature in humans has been derived from other vertebrate species.
metabolic differences, individual fibres can be classified as oxidative However, where direct comparisons with the developing human embryo
slowtwitch (red) fibres or glycolytic fasttwitch (white) fibres. Muscles have been made, the patterns and mechanisms of muscle formation
composed mainly of oxidative slowtwitch fibres correspond to the red have been found to be the same.
muscles of classical descriptions. Muscles that are predominantly oxida The majority of the skeletal muscle in the body develops from parax
tive in their metabolism contract and relax more slowly than muscles ial mesenchyme and its segmental derivatives, the somites. A small
relying on glycolytic metabolism. This difference in contractile speed is portion forming the extraocular muscles is derived from prechordal
due in part to the activation mechanism (volume density of the sarco mesenchyme, which joins with the most rostral paraxial mesenchyme
tubular system and proteins of the calcium ‘switch’ mechanism), and and which has been demonstrated to have a myogenic fate. Skeletal
in part to molecular differences between the myosin heavy chains of muscle precursor myoblasts are derived from dermomyotomes, the
these types of muscle. These differences affect the ATPase activity of the lateral portion of the somites (see Fig. 44.3).
myosin head, which in turn alters the kinetics of its interaction with
actin, and hence the rate of crossbridge cycling. Differences between
Myogenic determination factors
myosin isoforms can be detected histochemically, and ATPase histo
chemistry continues to play a significant role in diagnostic typing (Table
5.1). Two main categories have been described: type I fibres, which are Myogenic determination factors, which can be detected in somites prior


slowcontracting, and type II, which are fastcontracting. Molecular to morphogenetic changes, are a family of nuclear phosphoproteins
analyses have revealed that type II fibres can be further subdivided that includes Myf5, myogenin, MyoD and Myf6 (herculin). They have
according to their content of myosin heavychain isoforms into types in common a 70aminoacid, basic helixloophelix (bHLH) domain
IIA and IIX. Muscle fibres may contain only one (i.e. a pure fibre) or a that is essential for protein–protein interactions and DNA binding.
combination (i.e. a hybrid fibre) of these isoforms; the five most preva Outside the bHLH domain there are sequence differences between the
lent muscle fibre types in humans are I, I/IIA, IIA, IIA/IIX, IIX. (For factors that probably confer some functional specificity. The myogenic
further reading, see Galpin et al (2012), Holland and Ohlendieck bHLH factors play a crucial role in myogenesis. Forced expression of
(2013).) There is a correlation between categories and fatigue resistance, any of them diverts nonmuscle cells to the myogenic lineage. They
such that type I fibres are generally oxidative (slow oxidative) and resist activate transcription of a wide variety of musclespecific genes by
ant to fatigue; type IIA are moderately oxidative, glycolytic (fast oxida binding directly to conserved DNA sequence motifs (–CANNTG–
tive glycolytic) and fatigueresistant; and type IIX largely rely on known as Eboxes) that occur in the regulatory regions (promoters and
glycolytic metabolism (fast glycolytic) and so are easily fatigued. enhancers) of these genes. Their effect may be achieved cooperatively
and can be repressed, e.g. by some protooncogene products. Some of
Fibre type transformation the bHLH proteins can activate their own expression. Accessory regula
Fibre type proportions in a named muscle may vary between individu tory factors, whose expression is induced by the bHLH factors, provide
als of different age or athletic ability. Fibre type grouping, where fibres an additional tier of control.


with similar metabolic and contractile properties aggregate, increases Myogenic factors do not all appear at the same stage of myogenesis
after nerve damage and with age. Grouping occurs as a result of rein (Buckingham et al 2003). In the somites, Myf-5 is expressed early,
nervation episodes, where denervated fibres are ‘taken over’ by a sprout before myotome formation, and is followed by expression of myogenin.
ing motor neurone and adopt its type properties. If the nerves to fast MyoD is expressed relatively late, together with the contractile protein
white and slow red muscles are cut and crossanastomosed in experi genes. Myf-6 is expressed transiently in the myotome and becomes the
mental animals, so that each muscle is reinnervated by the other’s nerve, major transcript postnatally. Whether this specific timing is important
the fast muscle becomes slowercontracting, and the slow muscle faster for muscle development is not yet clear. The creation of mutant (‘knock
contracting. There is evidence that such fibre type transformation may out’) mice deficient in the bHLH proteins has shown that myogenin
be a response to the patterns of impulse traffic in the nerves innervating is crucial for the development of functional skeletal muscle, and
the muscles (Minetto et al 2013). If fast muscles are stimulated continu that while neither Myf-5 nor MyoD is essential to myogenic differen
ously for several weeks at 10 Hz, a pattern similar to that normally tiation on its own, lack of both results in a failure to form skeletal
experienced by slow muscles, they develop slow contractile characteris muscle. In the limb bud the pattern of expression of the bHLH genes
tics and acquire a red appearance and a resistance to fatigue even greater is generally later than in the somite: Myf-5 is expressed first but tran
than that of slow muscles. siently, followed by myogenin and MyoD, and eventually Myf-6. These


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differences provide evidence at the molecular level for the existence of The initiation of fusion does not depend on the presence of nerve fibres,
distinct muscle cell populations in the limb and somites. It may be that since these do not penetrate muscle primordia until after the formation
the myogenic cells that migrate to the limb buds differ at the outset of primary myotubes.
from those that form the myotome, or their properties may diverge Although synthesis of the contractile machinery is not dependent on
subsequently under the influence of local epigenetic factors. fusion of myoblasts, it proceeds much more rapidly after fusion. Sar
comere formation begins at the Zdisc, which binds actin filaments
Formation of muscle fibres constituting the Iband to form I–Z–I complexes. The myosin filaments
assemble on the I–Z–I complexes to form Abands. Nebulin and titin
are among the first myofibrillar proteins to be incorporated into the
In both myotomes and limb buds, myogenesis proceeds in the follow
sarcomere, and may well determine the length and position of
ing way. Myoblasts become spindleshaped and begin to express
the contractile filaments. Desmin intermediate filaments connect the
musclespecific proteins. The mononucleate myoblasts aggregate and
Zdiscs to the sarcolemma at an early stage, and these connections are
fuse to form multinucleate cylindrical syncytia, or myotubes, in which
retained.
the nuclei are aligned in a central chain (Fig. 5.44). These primary
Myogenic cells continue to migrate and to divide, and during weeks
myotubes attach at each end to the tendons and developing skeleton.
7–9 there is extensive de novo myotube formation. Myoblasts aggregate
near the midpoint of the primary myotubes and fuse with each other
to form secondary myotubes, a process that may be related to early
Immigration neural contact. Several of these smallerdiameter myotubes may be
of myoblasts aligned in parallel with each of the primary myotubes. Each develops
a separate basal lamina and makes independent contact with the