Neurobiology 104 - 2003-09-30 Dr Geoff Meyer

Muscle

In vertebrates there is striated muscle or smooth muscle depending on the presence or absence of regularly repeating arrangements of contractile proteins. There are 2 types of striated muscle – skeletal muscle and cardiac muscle.

Skeletal muscles are under voluntary control.

Cardiac muscle resembles striated muscle in many respects, but is specialized

for the continuous, rhythmic involuntary contraction needed in the pumping of

blood.

Smooth muscle is under involuntary control.

Striated (skeletal) muscle

Skeletal muscle develops from mesoderm. Muscle fibers are multinucleate, resulting from the fusion and subsequent differentiation of unicellular myoblasts into long myotubes. These myotubes mature into a long muscle cell.

A skeletal muscle consists of a number of fasciculi, which are bundles of long

muscle fibers (cells), contained within a connective tissue (CT) sheath. So the muscle fibers are arranged parallel to each other with intervening spaces housing parallel arrays of capillaries as well as nerve axons.

Skeletal muscle is surrounded by three distinct layers of connective tissue:

Epimysium is the relatively dense CT surrounding the entire muscle.

Perimysium is derived from the epimysium and surrounds fascicles (i.e. bundles of muscle fibers).

Endomysium - is the delicate loose CT (reticular fibers) surrounding each muscle fiber; it contains numerous capillaries. A basement membrane (external lamina) surrounds each muscle cell.

Muscle fibers may be classified by color: red, white or intermediate.

Red fibers (chicken thighs) are small and contain large amounts of myoglobin, mitochondria and are rich in oxidative enzymes they do not have an extensive sarcoplasmic reticulum. Contraction of these fibers is slow, repetitive but weak and they do not easily fatigue and are typically found in the limb muscles of mammals. The muscles of marathon runners contain lots of red fibers.

White fibers (chicken breasts) are larger and contain less myoglobin and mitochondria. Their contraction is fast and strong but they fatigue easily. They are used to control fine movements such as the fingers and extraocular muscles of the eye. Sprinters have lots of white fibers in their leg muscles.

Intermediate fibers, as the name suggests, fall somewhere in between the other

two types.

A particular anatomical muscle such as the biceps has a relatively constant proportion of fibre types.

The length of the fibers varies, with some as short as 1 mm, and others up to

10cm long. Their diameter varies from 10 to 100µm. Each fiber may extend the

full length of a fasciculus, or may terminate within the substance of a bundle.

The connections from the different fascicles to the main tendon are via

interfascicular dense regular CT (i.e. subdivisions of the main tendon).

Long arrays of cylindrical myofibrils fill each muscle cell. Myofibrils are contractile organelles composed of highly organized arrays of myofilaments, which are the proteins responsible for the contraction of the fiber. They are aligned precisely and parallel with their neighbours which is responsible for the light and dark banding characteristic of skeletal muscle when viewed in longitudinal section. Surrounding the fibrils are the cytoplasmic components of the fiber, the sarcoplasm. Myofibrils are held in register with one another by intermediate filaments (desmin and vimentim). They secure the periphery of Z disks of neighbouring myofibrils to each other. Bundles of myofibrils are attached to the cytoplasmic aspect of the sarcolemma by various proteins including dystrophin.

The contractile apparatus

Even at the level of the light microscope, the regular structure of striated

muscle is evident: the dark A-bands alternate with the light I-bands, and each

I-band is bisected by a dark line the Z-disk. The light and dark bands are

perpendicular to the long axis of the muscle fiber, along which the muscle

contracts. The segment from one Z-disk to the next is termed a sarcomere, is about 2.5µ in length in resting muscle and considered the contractile unit of skeletal muscle fibers.

Each myofibril is constructed of a repeating array of sarcomeres. Each sarcomere contains two types of myofilaments - thick myosin filaments and thin actin filaments, as well as many other proteins which support, anchor and maintain the precise alignment of the thick and thin filaments to one another. One end of each thin filament is attached to the Z-disk. Thick filaments extend the entire width of the A-band (dark), while thin filaments extend from the Z-disk, across the I-band (light),

part way into the A-band. The area of the A-band which is free of thin filaments

is termed the H-band.

Movements of actin and myosin within each sarcomere lead to shortening of the

sarcomeres, and thus to shortening (contraction) of the muscle as a whole.

It is well established that muscle contraction is caused by the sliding of the

thick and thin filaments past each other. The length of a sarcomere decreases by

about a third. However the individual myosin fibers and actin filaments do not

change length during contraction. What does change is the width of the H and I

bands as the thin filaments slide over the thick filaments. The I band becomes narrower, H band is extinguished and Z disks move closer to each other.

Myosin has been shown to be a long, rod-like molecule, with two globular heads.

Each thick filament is composed of hundreds of myosin molecules, with their

heads sticking out at precise angles. These myosin heads make contact with the

adjacent thin actin filaments. During muscle contraction, the number of myosin

heads that are in contact with actin filaments, increases. The mechanical

tension that can be produced by a muscle depends on the amount of overlap

between the thick and thin filaments (i.e. how many myosin heads are in contact

with the actin thin filament).

The interactions of actin and myosin produce a coherent contractile force, as

chemical energy is converted into mechanical work. The energy for muscle

contraction comes from the hydrolysis of ATP to ADP + Pi which fuels a

conformational change in the myosin head. Contraction is accomplished by the

cyclic formation and breaking of bridges between myosin globular heads and the

sides of adjacent actin filaments. Bridge formation pulls the thin filaments

towards the center of the A-band, resulting in contraction of the sarcomere.

The binding of myosin to actin requires Ca²⁺. It is only when Ca²⁺ flows into

the fibril in response to a nerve impulse that a binding site on actin is

exposed and a cross-bridge can be formed between the myosin head and actin. As

long as the Ca²⁺ concentration is sufficiently high, the myosin-actin bridge

will cycle continuously and the muscle will contract.

All the myofibrils in a myofiber contract simultaneously. How is this

accomplished in very long muscles in which Ca²⁺ may have to diffuse long

distances? The chain of events leading from excitation of the nerve to muscle

contraction depends on important specializations of the muscle cell membranes

through which the signal is relayed. Each myofibril is surrounded by a meshwork

of smooth membranes termed the sarcoplasmic reticulum (SR). At the level of the

junction between the dark and light bands (A-I junction), the SR forms a

continuous flattened membrane channel called the terminal cisterna. At every A-I

junction, the sarcolemma (plasma membrane) of the fiber extends inward in a

series of tubules, to also surround each myofibril. These tubules are termed

transverse or T-tubules and are continuous with the sarcolemma. The two terminal

cisternae and a single T-tubule form a triad; there are two triads per

sarcomere—one at each A-I junction.

The SR serves as a reservoir of Ca²⁺, sequestered from the myofibrils. When a

neural impulse arrives at a fiber, depolarization of the plasma membrane occurs.

Within milliseconds, this depolarization propagates into the fiber along the

membranes of the T-tubules, and is transferred to the SR, resulting in the

release of large amounts of Ca²⁺ into the cytosol of the fiber. The resulting

rise in free Ca²⁺ initiates myofibril contraction. Because the signal from the

sarcolemma is passed (via the T-tubules) to every sarcomere in the cell within

milliseconds, every sarcomere contracts almost simultaneously. Continued

stimulation of the muscle keeps the cytoplasmic Ca²⁺ level high. When the

stimulation ceases, the Ca²⁺ is actively pumped back into the SR. Striated

muscles can undergo very rapid increases and decreases in the level of cytosolic

Ca²⁺, thereby permitting precise control of muscular movements.

Striated muscles fibers do not show degrees of contraction—they contract all the

way or not at all. In order to vary the force of contraction, not all of the

fibers will contract at the same time. So the strength of contraction of a gross anatomical muscle such as the biceps is a function of the number of muscle fibers that undergo contraction.

Innervation of skeletal muscle

Specificity of motor innervation is a function of the muscle innervated. The stimulus is transferred at the neuromuscular junction. The contact made by the terminal branches of an axon with the muscle is called the motor end plate. Together, the neuron and the muscle fibers it innervates is called a motor unit and the muscle fibers of a motor unit obey the “all or none” law of muscle contraction. A single motor neuron may contact from several to a hundred or more muscle fibers (eye muscle – abdominal muscles).

Muscle spindle.

Muscles contain specialized receptor units termed muscle spindles consisting of 8-10

specialized/modified muscle fibers (2 types of “intrafusal” fibers having centrally located nuclei) and both sensory and motor neuron terminals, surrounded by a connective tissue capsule. The muscle spindle monitors the position of the muscle and its degree of tension/stretch (ie. length and changes in length). The muscle spindle is an example of a proprioceptor, a structure that provide information about body position, muscle tone and movement.

Golgi tendon organs (neurotendinous spindles) are located at the junction of the muscle with its tendon. They monitor the force of contraction and (via feedback) relax muscle contraction and so this organ is a protective device for muscle, bone and tendon.

The information gathered in these receptors prevents injury due to over-contraction of the muscle.

Together these two receptors also supply input to the cerebrum and cerebellum supplying information about the body’s position in 3D space/precise motor control – as in touching your nose in a darkened room/ or with your eyes closed.

Cardiac muscle

Cardiac muscle is similar to skeletal muscle in many ways, consisting of long

fibers (cells) that are cross-striated. The contractile unit is the sarcomere.

The cross striations are due to the arrangements of thick myosin and thin actin

filaments which are attached to Z-disks. However the fibers of cardiac muscle

arise by differentiation and growth of single myoblasts, not by the fusion of

many myoblasts as is seen in skeletal muscle. Thus the myofibers of cardiac

muscle have only one or two nuclei, which are located centrally in the cell.

Cardiac muscle fibers also branch.

The changes in the structure of a sarcomere during contraction of cardiac muscle

are similar to those in skeletal muscle, as are the biochemical reactions

involving the release of Ca²⁺, attachment of the myosin head to actin,

hydrolysis of ATP etc. However, a major difference is seen in the input required

to initiate contraction: viz. skeletal muscle contracts only after an external

stimulus provided by the motor nerve ending, while cardiac muscle cells possess

the ability to contract rhythmically at an intrinsic rate in the absence of an

external stimulus.

A structural feature peculiar to cardiac muscle is the intercalated disk. These

are seen as cross bands by light microscopy. The intercalated disks are

end-to-end junctions between individual cardiac muscle cells. Since cardiac

muscle cells branch and connect to adjacent cells, the intercalated disks are of

different lengths. Intercalated disks have transverse portions that run

perpendicular to the long axis of the cell, and lateral portions that run

parallel to the long axis of the cells.

The transverse portions contain fascia adherentes and desmosomes. These

specialized junctions anchor the fibers together. On their lateral surfaces the

fibers are connected by gap junctions, which provide electrical coupling between

the cardiac muscle cells, thus contributing to a network of communicative

pathways over which the overall rhythmic activity of the heart is coordinated.

Actin filaments of the last sarcomere of each fiber insert into the intercalated

disk. Gap junctions also forms in regions where cells lying side by side come in close contact with each other.

The heart contains specialized cardiac muscle fibers called Purkinje fibers.

These cells are arranged into bundles and make up part of the impulse conducting

system of the heart. Purkinje fibers are larger than regular cardiac fibers,

contain fewer myofibrils and are rich in glycogen, which gives them a

pale-staining appearance.

Cardiac muscle will be revisited in your lecture on “Vascular system” this Thursday (October 2^nd).

Smooth muscle

Smooth muscle is the contractile component of the walls of most of the hollow

viscera of the body - i.e. the gut, bladder, uterus and the walls of bronchi,

blood vessels and the ducts of many secretory glands. In bundles of smooth

muscle, the cells overlap one another along their length. The bundles are

normally organized into layers—however smooth muscle cells are frequently found

as isolated units scattered in connective tissue of associated with secretory

glands.

Smooth muscle consists of spindle-shaped cells which range in length from 20 to

200µm. The cells, which are also called fibers, are thickest in their midregion and

taper at each end. Each cell is surrounded by a basal lamina, except at the gap

junctions between cells. They are also surrounded by reticular fibers and

elastic fibers, both of which are secreted by the smooth muscle cells. In

contrast to cardiac muscle, smooth muscle can regenerate in response to injury.

The contractile elements are myofilaments, but they are not arranged in the

ordered manner of those in striated muscle, and there are no

sarcomeres. In a few smooth muscles, every cell receives individual innervation

(e.g. iris of eye), but in the majority only a few muscle cells in a bundle are

equipped with neuromuscular junctions. In these muscles, impulse transmission

occurs via gap junctions, which allows the spread of excitation to neighboring

cells.

Smooth muscles are not under voluntary control and are specialized for slow

sustained contraction, without fatigue. Contraction may occur in a wave-like

manner, producing peristaltic movements as in the GI-tract, or it may contract

all at once, as in the bladder or uterus.

Smooth muscle contains actin and myosin II filaments, but they are not arranged

in the regular pattern seen in skeletal muscle fibers. Rather they are arranged

in a latticework that also contains intermediate filaments. The actin and

intermediate filaments insert into cytoplasmic dense bodies that anchor to the

plasma membrane, and which are rich in a-actinin. These are analogous to the

Z-lines of the sarcomere. Smooth muscle contraction is initiated by the entry of

Ca²⁺ through voltage gated channels in the cell membrane. This Ca²⁺ binds to the

protein calmodulin which can then bind to and activate myosin light chain kinase

(MLCK). Activated MLCK causes the phosphorylation of myosin light chain, thus

allowing it to bind to actin, and initiating muscle contraction. When myosin is

dephosphorylated, in response to decreased Ca²⁺, the myosin head dissociates

from actin and the muscle relaxes. Smooth muscle cells are capable of sustained

contraction over a long period of time, utilizing small amounts of ATP. Although

most smooth muscle contraction is regulated by neuronal stimulation, they are

also capable of spontaneous contraction in the absence of neural input, as well

as by hormonal stimulation (e.g. oxytocin). The nerve supply has the function of

modifying activity, rather than initiating it, as in skeletal muscle

Regeneration of muscle

The number of muscle fibers does not increase significantly after birth.

Increase in the overall size of a muscle is then brought about by the formation

of more myofilaments. (Since we cannot increase the number or type of muscle

fibers after birth, if you want to be an Olympic athlete, you need to pick your

parents very carefully).

If damaged, skeletal muscle fibers can regrow because a pool of inactive stem cells

(satellite cells) lies just beneath the external lamina of the muscle fiber.

These cells are stimulated to divide and fuse with the muscle fiber if the

muscle is stressed or damaged. There is also a population of cells (side population cells) in bone marrow that have the potential to participate in skeletal muscle regeneration.

Cardiac muscle is incapable of regeneration. Damaged cardiac muscle is replaced by scar tissue (fibrous connective tissue).

Smooth muscle cells retain their mitotic activity but can also differentiate from pericytes.

Myoepithelial cells.

Certain modified epithelial cells associated with glandular secretion possess

contractile activity. These myoepithelial cells wrap around the secretory

portion of glands and contract in response to hormonal (e.g. oxytocin in the

breast) or neurotransmitter release, to help expel the contents of the secretory

gland to the exterior. Myoepithelial cells also form the dilator muscle in the

iris of the eye. Contraction of myoepithelial cells occurs in a manner similar

to that described for smooth muscle.