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Skeletal Muscle I
Basic Features of Vertebrate Skeletal
Muscle
• Filaments organized as sarcomeres (I.e.
striated)
• Cells large ( 200 micron diameter, up to
meters long), polynuclear, formed by endto-end fusion of myocytes during
development.
• Single, mononeuronal innervation (Ach,
nicotinic receptors)
Tissue-level structure breakdown
Muscle (consisting of many cells/fibers) bounded
by epimysium
Muscle fascicles (bundles) bound by perimysium
Each fiber surrounded by endomysium = basal lamina
which supports capillaries and axon terminals
Each fiber has a sarcolemma=plasma membrane
Within the fiber there are two separate
functional compartments:
The cytoplasmic compartment
containing several myofibrils
composed of sarcomeres end-toend, + mitochondria, etc.
Surrounded by a network of hollow
tubes of sarcoplasmic reticulum
(a specialized endoplasmic
reticulum)
The Contractile Machinery
This electron micrograph shows several complete
sarcomeres of adjacent myofibrils
Major protein components of thin
filaments
•
•
•
•
Actin: backbone + myosin binding sites
tropomyosin: regulates myosin access
troponin: binds Ca++ ; controls tropomyosin
nebulin: believed to serve as a scaffold for
assembly of thin filaments and as a
molecular yardstick that regulates their
length.
The sarcomere is the basic functional
unit of striated muscle
This cartoon shows
the thin-filament
components listed in
the previous slide
and also shows titin,
a protein that links
the ends of thick
filaments to the Z
disc
Contraction of
striated muscle
involves sliding of
thick and thin
filaments.
Implications of the
sliding filament
mechanism are seen
in experiments in
which the lengthtension relationship
of muscle is
measured, as shown
in the next slide.
The total tension is the sum of an active and a passive
component. The active component is maximal when
overlap of thick and thin filaments is optimal.
Much of the
elasticity of
the passive
muscle is now
believed to be
due to titin.
Neural control of skeletal muscle
excitation
Organization of motor systems
Subdivision
Of PNS
Ganglionic
synapse
Target tissue synapse
Somatic
none
Ach; nicotinic r.
Sympathetic
Ach, nicotinic r.
Norepinephrine;
alpha or beta
adrenergic r.s
Parasympathetic
Ach; nicotinic r.
Ach; muscarinic r.
Points to remember
• Acetylcholine is always the transmitter at the first synapse
outside the CNS
• Nicotinic receptors are always at the first synapse outside
the CNS, are ionotropic and always excitatory.
• In the parasympathetic pathway, acetylcholine is also the
transmitter at the target organ, although other mediators
may be coreleased (bombesin, for example).
Parasympathetic target organs have muscarinic receptors
for Ach (5 subtypes –all are metabotropic and may be
excitatory or inhibitory)
• The transmitter at sympathetic target organs is always
norepinephrine; the receptors may be one or more of the
four basic adrenergic receptor types (alpha1, alpha2, beta1,
beta2 – these are all metabotropic and may be excitatory or
inhibitory)
Excitation-Contraction Coupling
Skeletal Muscle Excitation: Facts
• There is a 1:1 relationship between neuronal and muscle
APs
• Following an AP, a pulse of Ca++ in the muscle cytoplasm
starts within a few msec and lasts for at least tens of msec this causes the contractile machinery to become active. The
[Ca++] achieved around the contractile machinery is
enough to activate all (or almost all) of the contractile
machinery.
• The next slide shows the relationship between electrical
excitation, Ca++ release, and tension development
In this experiment, the muscle is loaded with a probe whose
fluorescence is quenched by Ca++. Notice that force
development does not seem to begin until Ca++ levels have
already begun to fall, and continues after [Ca++] has returned
to baseline. This is the result of energy storage in the muscle’s
series elastic elements.
Motor neurons talk to skeletal
muscles in bursts of action potentials
that result in smooth, sustained
contractions
• The next slide shows an experiment in
which a twitch – the result of 1 AP – is
compared to the tetanic contraction caused
by a train of action potentials
The Ca++ pulse from 1
AP lasts longer than
the electrical refractory
period - allowing
successive Aps to
summate their
contractile effects,
giving a tetanus, or
smooth contraction
The Problem Of Synchronizing the
Contractile Machinery
• the muscle AP spreads throughout the cell
membrane within a few msec, BUT - how
does an electrical signal at the cell surface
cause myofibrils in the interior of the cell to
become active? - fiber diameter is too great
for a chemical signal crossing the cell
membrane and diffusing to the central
myofibrils to give the rapid onset and offset
of contraction that we observe.
The Solutions
• Transverse tubules of cell membrane
penetrate the cell surface at intervals of 1
sarcomere length, carrying the electrical
signal to the cell interior.
• There is a store of Ca++ inside the SR.
• T tubules pass close to the lateral cisternae
of the SR; a T-tubular AP causes Ca++
release within the muscle fiber.
The square marks a muscle triad: a central T
tubule with a lateral cisterna on each side.
The drawing shows an enlargement of the
relationship between T tubule and lateral cisternae.
Note the endfeet that seem to connect the two.
How does a T-tubular AP cause the SR to
release Ca++? A pop-up hypothesis.
Endfeet consist of
1. A voltage-sensitive channel protein in the T-tubular
membrane (the dihydropyridine receptor), sitting
above
2. a Ca++ channel in the SR membrane (the ryanodine
receptor).
The DHP receptor serves as a voltage sensor that plugs
the ryanodine receptor with its cytoplasmic domain when
the T tubule is normally polarized, and lifts the stopper
upon depolarization, allowing Ca++ to diffuse out down its
concentration gradient.
The initial Ca++ release triggers
additional Ca++ release
Since only half of the endfeet have voltage
sensors, it is currently believed that the initial
Ca++ release triggers the opening of additional
Ca++ release channels, a process called Ca++induced Ca++ release.
The Ca++ switch for muscle contraction
Tropomyosin- threads of tropomyosin lie along the
thin filament. In the relaxed muscle each tropomyosin
blocks a series of 8 binding sites for myosin heads.
Troponin- a 3-subunit troponin controls each
tropomyosin. As shown in the next slide, Ca++-binding
to the C subunit of troponin causes a conformational
change in the troponin that rolls or pulls tropomyosin
away from the myosin binding sites.
Relaxation is the result of Ca++ recovery
back into the SR by active transport - there is
a Ca++-ATPase in the SR membrane. The
level of activity of this enzyme determines
twitch duration.
Accumulation in the cisternae is aided by the
presence of a Ca++-binding protein called
calsequestrin that is present specifically
within the cisternae.