Physiology for MRCEM Primary

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Basic cellular physiology

Skeletal and smooth muscles

Muscle morphologies

[box type=”download”]  An appreciation of the functional purposes of skeletal, smooth and cardiac muscle [/box]
There are three types of muscle: skeletal (muscle attached to the skeleton); cardiac (muscle in the heart) (both of these are morphologically striped and are commonly called striated muscles); and smooth (muscle involved in many involuntary processes in blood vessels, airways and gut; this type is not striated, hence its name).

Skeletal muscle

[box type=”download”]  Its composition [fasciculi, fibres, myofibrils] and the concept of functional units  The sarcolemma and sarcoplasmic reticulum as prime membrane components  Contraction as occurring via thick and thin filaments  Simple understanding of excitation – contraction coupling as the basis of contraction  Roles of calcium and ATP in effecting contraction  Concepts of temporal and spatial summation, motor units and recruitment of units  Detailed knowledge of contractile mechanisms (eg intracellular signalling) is NOT required[/box]

It uses about 25% of our oxygen consumption at rest and this can increase up to 20-fold during exercise.
Epimysium(connective tissue) covers whole muscle and eventually blends into a tendon.
Skeletal muscle is composed of numerous parallel, elongated, multinucleated (up to 100) muscle fibres or myofibres, which are between 10 and 100 μm in diameter and vary in length, and are grouped together to form fasciculi.
Each fasciculus is surrounded by the perimysium.
Each myofibre is encased by connective tissue called the endomysium.
Beneath the endomysium is the sarcolemma (excitable plasma membrane). This has infoldings that invaginate the fibre interior, particularly at the motor end plate of the neuromuscular junction.
Each myofibre is made up of myofibrils 1 μm in diameter separated by cytoplasm and arranged in a parallel fashion along the long axis of the cell.
Each myofibril is further subdivided into thick and thin myofilaments (thick, 10–14 nm in width, 1.6 μm in length; thin, 7 nm in width, 1 μm in length). These are responsible for the cross-striations.
Thin filaments consist primarily of three proteins, actin, tropomyosin and troponin, in the ratio 7:1:1, and thick filaments consist primarily of myosin.

The cytoplasm surrounding the myofilaments is called the sarcoplasm.
Each myofibre is divided at regular intervals along its length into sarcomeres separated by Z-discs (in longitudinal sections, these are Z-lines).
To the Z-lines are attached the thin filaments held in a hexagonal array.
The I-band extends from either side of the Z-line to the beginning of the thick filament (myosin).
The myosin filaments make up the A-band.
The H-zone is at the centre of the sarcomere, and the M-line is a disc of delicate filaments in the middle of the H-zone that holds the myosin filaments in position so that each one is surrounded by six actin filaments.

The thin filaments consist of two intertwining strands of actin with smaller strands of tropomyosin and troponin between them. Each strand of actin has globular or G-actin containing binding sites for myosin.
At rest, these sites are covered by tropomyosin preventing myosin binding.

The thick filaments are made up of about 100 club shaped myosin molecules.
The ATPase activity is in the head of club.
The thin tails of the myosin molecules form the bulk of the thick filaments, whereas the heads are ‘hinged’ and project outward to form cross-bridges between the thick filaments and their neighbouring thin filaments.
Six thin filaments surround each thick filament.

The transverse or T-tubules contain extracellular fluid.
The specialized smooth endoplasmic reticulum, the sarcoplasmic reticulum (SR), is enlarged to form terminal cisternae close to the T-tubules. Ca2+ is transported from the cytosol into the SR by the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA).

The interaction of actin (thin filaments) and myosin (thick filaments) brings about contraction of the muscle, which is caused by the cross-bridges, a result of the interaction of troponin and Ca2+.
This mechanism is called the sliding filament theory.
The contraction of muscle is triggered by release of Ca2+ from the SR.
Ca2+ floods out of the cisternae, where it is stored by binding reversibly with a protein, calsequestrin.
This raises the concentration of calcium from 0.1 μmol/L to more than 10 μmol/L, saturating the binding sites on troponin.
This results in a shift of tropomyosin, thus allowing myosin cross-bridges to bind with actin and begin the contraction cycle.
The heads tilt after attachment by hydrolysing the ATP, which leads to a greater binding of the cross-bridges.
This releases the binding of the head and, if Ca2+ is still present, the cycle continues. Otherwise, the binding is inhibited.
Contraction is maintained as long as Ca2+ is high.
The duration of the contraction is dependent on the rate at which SERCA pumps the Ca2+ back into the SR.

Neuromuscular junction (NMJ)

The neurones that innervate skeletal muscles are called α-motor neurones which make connections with the motor end plate, and together form the neuromuscular junction (NMJ)
The motor neurone axon terminal has acetylcholine (ACh) in vesicles.
A few vesicles release their contents by exocytosis at rest.
ACh diffuses across the cleft and reacts with nicotinic receptors in the postsynaptic membrane (motor end plate).
These receptors contain an integral ion channel, which opens and allows influx of small cations, mainly Na+.
This generates an end plate potential (EPP) causing 0–4-mV depolarizations, called miniature end plate potentials (MEPP).

However, when an action potential reaches the prejunctional nerve terminal, there is an enhanced permeability of the membrane to Ca2+ ions due to opening of voltage-gated Ca2+ channels. This causes an increase in the exocytotic release of ACh that produces an EPP that is above the threshold for triggering an action potential in the muscle fibre.
The effect of ACh is rapidly abolished by the activity of the enzyme acetylcholinesterase (AChE).
ACh is hydrolysed to choline and acetic acid.
About one-half of the choline is recaptured by the presynaptic nerve terminal and used to make more ACh.

Whole muscle contraction

As the action potential spreads over the muscle fibre, it invades the T-tubules and releases Ca2+ from the sarcoplasmic reticulum into the sarcoplasm, and the muscle fibres contract.
This contraction will be maintained as long as the levels of Ca2+ are high.
The single contraction of a muscle due to a single action potential is called a muscle twitch.
Fibres are divided into fast and slow twitch fibres depending on the time course of their twitch contraction.
This is determined by the type of myosin in the muscles and the amount of sarcoplasmic reticulum.
Isometric contraction occurs when the two ends of a muscle are held at a fixed distance apart, and stimulation of the muscle causes the development of tension within the muscle without a change in muscle length.
The active tension developed is dependent on the length of the muscle.
The optimum length occurs where the thick and thin filaments are thought to provide a maximum number of active cross-bridge sites for interaction (close to the resting length of a particular muscle).

The single motor neurone and all the fibres it innervates (5-2000) is called the motor unit. This is the smallest part of a muscle that can be made to contract independently of other parts of the muscle.
The ratio between the number of α-motor neurones and the total number of skeletal muscle fibres is small in muscles such as the extraocular muscles that provide fine smooth movements (1 : 5), but large in muscles such as the gluteus maximus that need to generate powerful but coarse movements (1 : >1000).

During graded contraction, the smallest cells discharge first and the largest last (the so-called size principle).
The tension developed by the first action potential has not completely decayed when the second contraction is grafted on to the first, and so on. This is called summation.
If the muscle fibres are stimulated repeatedly at a faster frequency, a sustained contraction results in which individual twitches cannot be detected. This is called tetanus.
When there is a need to gradually decrease the force output, the pattern is reversed, so that those units that were recruited last will be the first to decrease their firing and then stop, and the last units to fire will be the smallest units.
Because the unitary firing rates for each motor unit are different and not synchronized, the overall effect is a smooth force profile from the muscle.
When synchronized firing does occur, such as in fatigued states and Parkinson’s disease, marked muscle tremors are seen.
The summed excitatory impulses (action potentials) of the motor units can be recorded in an electromyogram (EMG).