MUSCLE lectures Ali Hussein

Skeletal muscles are composed of many long, thin cells called muscle
fibres, grouped in parallel bundles called fascicles. The individual fibres are held
together in the fascicles by a thin connective tissue called ENDOMYSIUM, with
the fascicles surrounded by a thin connective tissue called PERIMYSIUM. The
entire muscle is surrounded by a connective tissue called EPIMYSIUM.
Each muscle fibre is a cell formed by the fusion of a large number of precursor cells called
myoblasts, each of which contributes a nucleus forming a multinucleate myofibril. The main
components of a muscle are these myofibrils surrounded by sarcoplasmic reticulum, T tubules and
mitochondria. A few of the myoblasts are left over and form single SATELLITE CELLS. The segment of
a myofibril stretching from one Z-line to the next is known as a SARCOMERE, each sarcomere being
~2-3μm long.
The Neuromuscular Junction is the synapse between a motor neurone and a skeletal muscle
fibres, using Acetylcholine as a transmitter. The post-junctional membrane, the SARCOLEMMA in this
case, under the boutons is highly folded with many Nicotinic Acetylcholine Receptors on the crests of
these folds. When stimulated by the transmitter, the channels allow Na+, K+, and some Ca2+ ions to
flow across the membrane down their electrochemical gradients, and the fast inward movements of
Na+ ions results in a local depolarisation of the sarcolemma known as the END PLATE POTENTIAL
(EPP). The EPP raises the membrane potential, and once the membrane potential has reaches
threshold through summation of many EPP, then Voltage Gated Na+ channels open giving rise to an
Action Potential.
Muscle Action Potentials trigger contraction through a chain of events known as EXCITATION-
CONTRACTION COUPLING. This mechanise ensures that all parts of the cell are activated almost
simultaneously to allow for optimum contraction. Each myofibril is surrounded by a thin sleeve of
SARCOPLASMIC RETICULUM, containing a high concentration of Ca2+ ions, and a system of T-
TUBULES lies in between the myofibrils. These T-Tubules carry a modified action potential form the
sarcolemma deep into the fibres where they trigger the release of Ca2+ ions from the Sarcoplasmic
Reticulum. This is done at special points the muscle fibres known as TRIADS, typically found between
the A and I bands.

ACTION POTENTIAL PROPAGATES ALONG SACROLEMMA AND TRAVELS DEEP INTO FIBRE
DOWN T-TUBULES
↓
ACTION POTENTIAL REACHS TRIADS CAUSING RELEASE OF Ca2+ FROM SARCOPLASMIC
RETICULUM CHANNELS
↓
CALCIUM IONS BIND IN TROPONIN, CAUSING A CONFORMATIONAL CHANGE, TO RELOCATE
TROPOMYOSIN MOLECULES AND EXPOSE ACTIN FILAMENT TO MYOSIN FILAMENT.
↓
MYOSIN HEAD WITH BOUND ATP BINDS WITH ACTIN
↓
ATP SPLITS FROM THE MYOSIN, CAUSING MYOSIN HEAD TO UNDERGO A CONFORMATIONAL
GANED, STRETCHING THE FLEXIBLE PARTS OF THE HEAD AND NECK.
↓
THE RELEASE OF THE ADP+Pi IS COUPLED TO THE RELEASE OF STRAIN ENGERY AS MYOSIN
PULLS ACTIN TOWARDS THE CENTRE OF SARCOMERE.
↓
A NEW ATP MOLECULE BINDS TO THE HEAD.
↓
EVENTUALLY THE SARCOPLASMIC RETICULUM CALCIUM CHANNELS CLOSE
↓
CALCIUM IONS TAKEN UP INTO SARCOPLASMIC RETICULUM BY ATP-DRIVEN PUMP
There is no storage mechanism for ATP, so ATP is always syntheised on demand, either by:
• Rapid formation from CREATINE PHOSPHATE (CrP + ADP  ATP + Cr)
• Slower formation from ANAEROBIC GLYCOLYSIS, producing Lactic Acid. This method cannot
support longer activity due to the negative effects of increased intracellular [H+].
• Formation from AEROBIC METABOLISM that is more economical as it is maintained for hours.
•
When a muscles contracts, it either shortens or produces force. If the muscle remains at an overall
constant length it is called an ISOMETRIC contraction. If the
muscle shortens it is called a CONCENTRIC contraction, and if the
muscle stretches by action of an antagonist, it is called an
ECCENTRIC contraction.
The longer the muscle, the longer the sarcomere, so the less the
overlap and the less the force. At shorter lengths there is overlap
but the myosin-actin contact is less effective. Therefore there is an
optimum sarcomere length at which the muscle produces
maximum tension. This relationship is present on a LENGTH-
TENSION CURVE.

A TWITCH is normally recorded under isometric conditions, so only force changes, but in muscle, the
force of contraction last much longer than the Action Potential which triggers it. The twitch of slow
muscle fibres (which shall be described later on) is much longer (0.3s) than a twitch from fast fibres
(0.12s).
A rapid series of Action Potentials is needed to stimulate the muscle and sustain contraction. To ensure
this, the Ca2+ pumps must not complete the reuptake of Calcium, maintaining high sarcoplasmic Ca2+
levels to allow contraction to continue until the last Action Potential has finished. This sustained
contraction is known as a TENTANUS. The only muscle that cannot be tetanised is Cardiac Muscle,
since its Action Potential is the same duration as its contraction.

The minimal contractile unit is the MOTOR UNIT, composed of one motor neurone and all the muscle
fibres it innervates. Action potentials travelling along the motor axon, from the spinal cord, invade all the
terminal branches of the axons to reach the innervated muscle fibres more or less simultaneously.

Force is regulated either in short term, via MOTOR UNIT RECRUITMENT, in which the number of
activated motor units in a muscle vary; or long term, by increasing the muscle fibre diameter by training.

There are three types of Muscle Fibres with corresponding Motor Units: S= Slow
SLOW Type 1 SO Muscle Fibres are found in SR Motor Units. F= Fast
FAST Type 2A FOG Muscle Fibres are found in FR Motor Units. O = Oxidative
FAST Type 2B FG Muscle Fibres are found in FF Motor Units. R= Fatigue Resistant
G= Glycolytic
Type 2 Fibres are faster contracting fibres, capable of the highest rates of ATP F= Fatiguable
hydrolysis, and tend to have the highest capacity for Aerobic glycolysis, since it
produces ATP at the highest rate.
Type 1 Fibres are slower contacting fibres that hydrolyse ATP at a lower rate, but have a lower tension
cost, making them better equipped for aerobic metabolism. A lower tension cost means that less ATP is
used for the force developed.

Muscle Fatigue come in two forms:

CENTRAL FATIGUE is caused by a number of factors, such as prolonged mental activity, hard physical
labour, monotonous work, poor motivation, illness and neuronal damage. Central fatigue can be
instantly relieved by changing the activity and environment.
MUSCULAR FATIGUE involves an abnormally rapid onset of fatigue, and occurs due to a variety of
causes. Muscular Fatigue rarely occurs at the Neuromuscular Junction, but pathological conditions that
affect Acetylcholine release or Acetylcholine receptor numbers can lead to failure of neuromuscular
transmission. Partial failure of Excitation-Contraction Coupling via an efflux of K+ ions due to Action
Potentials can result in a local rise in K+ concentration in the lumen of T-tubules. This increased K+
concentration can depolarise the membrane and lead to a failure of Action Potential propagation and
the failure to open Sarcoplasmic Ca2+ channels. However, this effect is very short lived. Fibres that lack
mitochondria and are therefore usually involved in Anaerobic Respiration are Fatigable, and fibres with
many mitochondria are known to be Fatigue Resistant. Muscles with a poor blood supply or prolonged
disuse result in a substantial reduction in capillary supply and mitochondria numbers. Muscle activity
involved eccentric contractions can cause significant muscle damage leading to DELAYED ONSET
MUSCLE SORENESS, which reaches its maximum intensity after 24-48 hours.

MYOGENESIS is the formation of muscle, first by the fusion of myoblasts to give multinucleate muscle
fibres, and then for nascent fibres to start to synthesis contractile proteins that assembly into filaments
and myofibrils. These myofibrils become innervated by motor axon terminals and their nucleases
migrate to the subsarcolemmal position. This allows for the fibres to grow in diameter and length
through hypertrophy. New fibre formations, known as HYPERPLASMIA, occurs during fetal growth, and
any later growth is by hypertrophy only. However, Satellite cells can be stimulated to proliferate to form
new myoblast cells if a mature fibre is damaged.

CARDIAC MUSCLE
Cardiac muscle is also striated like Skeletal Muscle, but only has one nucleus, sometimes two. Cardiac
muscle fibres contain less sarcoplasmic reticulum, so the entry of Ca2+ ions from the extracellular space
triggers further Ca2+ release from the Sarcoplasmic reticulum, a mechanism known as CALCIUM
INDIUCED CALCIUM RELEASE. The cardiac muscle cells are linked together both mechanically and
electrically by structures known as INTERCALALATED DISKS. These are essential as the wave of
electrical activity which triggers contraction has to sweep round the heart from cell to cell. An action
potential which triggers contraction of individual fibres originates from pacemaker cells. As a result, the
force of contraction is graded in relation to intracellular Ca2+ concentration. Cardiac muscle force is
also affected by fibre length, with relatively short fibre lengths producing optimum force.

SMOOTH MUSCLE CELLS

Smooth Muscle is composed of spindle shaped cells with a single nucleus but
no striations. The cells are linked to each other both mechanically, at
membrane dense areas, and electrically, at gap junctions. Single Unit Smooth
Muscle have few synaptic contacts but have many gap junctions. Multi-Unit
Smooth Muscle has synaptic contacts on every cell, but few gap junctions.
There is much less myosin in striated muscle, with myosin filaments lying
between long actin filaments in small randomly orientated bundles. Filaments
attach onto dense bodies interconnected by intermediate filaments allowing for
greater relative shortening, but slower shortening. Smooth muscle cells contain little sarcoplasmic
reticulum and no troponin on the thin filaments, meaning most of the Ca2+ enters from extracellular fluid.
The intracellular Ca2+ concentration regulates the strength of contraction, and the extrusion of calcium
via pumps and exchangers is more important than reuptake into the sarcoplasmic reticulum. The
release of Ca2+ is stimulated either electromechanically, via depolarisation, or pharmacomechanically,
via transmitters or hormones.
In a PHASIC Contraction, the rise in Ca2+ concentration and the phosphorylation of myosin and force
achieved are tightly coupled together.
In a TONIC Contraction ,the force and lengthen of a contraction is much greater than expected for the
Ca2+ concentration and is a more economical method of contraction for long periods.