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Module 632
Lecture 9 JCS
Control of
Muscle Contraction
MODULE - 632
Lecture 8
Muscle Contraction
Lecture outcomes:
At the end of this lecture a student will be aware how :
1) most muscles are activated (sometimes inhibited) by neural
control.
2) single impulses produce a twitch; multiple impulses a tetanus
3) impulses reach the motor end plate, a modified synapse
•
5) this causes the muscle action potential to spread along the
sarcolemma,
•
6) propagation through the sarcolemma, into the T-tubules and
the SR causes release of calcium into the sarcoplasm
•
7) in skeletal muscle this binds to the troponin complex and
activates muscles
•
8)
smooth muscle is regulated.
•
9)
insect flight muscle are activated by calcium and stretch
•
10) molluscan muscles are regulated by Ca2+ binding to myosin
Muscle regulation (1) Vertebrate striated muscle
Vetebrate skeletal muscle (skeletal and cardiac) is
activated (regulated) by neuronal signals.
In addition there may be modulation by hormones etc.
A single axon activates many fibres
Innervation types
Not all muscle fibres are “all or none” – but most are!
a) single motor unit with one (or
sometimes two) endplate: all-ornothing electrical response. Vert. fast
twitch fibres.
b) multi-terminal innervation:
usually graded electrical responses
like synaptic potentials, variable in
magnitude. Vert. ‘slow’ fibres (most
amphibian fibres); many invert.
muscles.
Number of fibres/axon varies:
‘Fast’ muscles - 1000-2000
fibres/axon
‘Slow’ muscles 180-200
fibres/axon
c) polyneuronal innervation.
Several nerves to one muscle:
different response from the different
nerves, - fast, slow and inhibitory.
note: excit. and inhib. control; fish,
many invert. (jump).
Twitch and tetanus – depend upon pattern of nerve impulses
Force
Tetanus
Unfused tetanus
Twitch
Time – sec.
3-D section of a skeletal muscle cell
SR
T-tubule
Ryanodine
receptor
Dihydropyridine
receptor
Cytosol
The dihydropyridineryanodine receptor complex
Regulation: Control by nerves (striated muscle)
• Summary:
– Neuromuscular junction
•
•
•
•
•
•
Muscle plasma membrane depolarises
Propagates down ‘T’ tubules
Trhough di-hyropyridine receptor  ryanodine receptor
into sarcoplasmic reticulum (SR) at centre of fibre
Calcium release from SR - induces calcium release
Ca++ binds to Troponin C – which moves Troponin I –
pushes tropomyosin – reveals actin binding sites –
myosin can bind and cycle, producing contraction.
7-actin repeat structure (14 - F-actin helix is double) in thin
filament
Structure repeats (half-turn) every 36.5nm
Relaxed state (muscle not contracting):
• TnI is bound to actin; holds TM over actomysin binding sites
• TnC has no Ca2+ bound to its regulatory sites.
• Tropomyosin lies across myosin binding site on F-actin.
Activation:
• Calcium binds to TnC, causing a conformational change in
TnC,
• Changes binding relationship of TnC and TnI relieving the
binding of TnI to actin.
• Tn-TM complex now free to move across the actin surface
• Movement, co-ordinately through TM ‘opens’ up a large
number (>7) of actins to the binding of myosin.complex
• Muscle contracts
Ca2+
+
Ca2+
In the absence of
Ca2+ the C-terminus
of TnI binds to actin,
holding the Tm-Tn
complex over the
myosin binding site
on actin.
When Ca2+ binds to
TnC, the C-terminus
of TnI binds to TnC,
Tm-Tn complex
moves across the
actin surface, and
the myosin can bind
producing
contraction.
Figure
from Berchtold et al.,
(2000)
Three state model of thin filament regulation - Geeves
Smooth muscle regulation (1):
Occurs through phosphorylation:
• Calcium released into smooth muscle cells
binds to calmodulin (homologous structure to
TnC);
• This binds to and activates myosin light chain
kinase (MLCK)
This phosphorylates the RLC leading to:
• Activation of myosin ATPase (changes kinetics
of the product – ADP + Pi – release steps)
• Increases assembly of thick filaments (see next
slide)
Smooth muscle regulation (2):
Remember smooth muscle has a rather poor
ultrastructure.
Smooth muscle myosin monomers change
solubility depending on its phosphorylation state.
In some smooth muscles this is a method of
regulation of contraction:
Dephosphorylated sm-myosin monomer has a
tendency to fold up (10s) and exist in a soluble
long-lived, inactive M.ADP state;
On phosphorylation it becomes extended (6s)
and assembles into thick filaments
Smooth muscle regulation (3):
Activation is achieved by increases in cytosolic calcium:
Usually caused by neural signals but often coupled to:
• Hormones binding to the -receptors
• Hormones and other external factors binding to  receptors, increasing cAMP levels
• cAMP reduces MLCK activity, reduces muscle
activity
• Different smooth muscles may react differently to the
same stimulus due to presence of different receptors:
• e.g. adrenalin – contraction of blood vessels to gut, but
dilation of coronary arteries (for flight and fight)
• caldesmon – Ca2+-binding, may function like Troponin.
Insect flight and Molluscan catch + adductor
muscles:
Pecten maximus
Insect flight muscles
Catch muscle
Adductor muscle
Regulation of molluscan muscle: (adductor)
Washed molluscan muscle (e.g. scallop) contains little troponin
The myofibrils retain calcium sensitive activation
Remove regulatory LC - Ca2+ sensitivity is lost.
Myosin contains two Ca-binding sites, both essential for regulation.
Neither RLC or de-sensitised myosin have a high affinity or specific Cabinding site.
Where does Ca2+ bind to activate?
Recent crystallographic studies shows that it binds between the ELC
and RLC; when both present the site is created.
Regulation of molluscan muscle: (catch)
Muscle completes contraction but maintains force. One explanation is
that Pi is released but not ADP. Myosin remains in a force-producing
state – but requiring no energy – until slight release of tension, allows
ADP to dissociate and the crossbridge to bind ATP and detach).
Adductor
MOLLUSCAN
Catch
state?
Catch muscle
S1 HEAD
Rayment et al.,
1993
MHC: (N to C terminal) Green – 27K domain; red – 50K domain (upper
and lower); blue 20K domain and lever;
ELC – yellow; RLC pink
Drosophila indirect flight muscles
(dorso-longitudinal muscles)
Insect indirect
flight muscles
Indirect because
not attached to the
wings; they move
the wings by
distorting the
thorax
Dorso- longitudinal
muscles -DLM
Dorso-ventral
Muscles -DVM
Jump-muscle
Tergal depressor
of trochanter TDT
Flight muscle – oscillatory and asynchronous
• Two muscle groups
- DVM dorso-ventral muscles
- DLM dorso-longitudinal muscles
• Requires Ca2+ activation – but nerve impulses are not in
synchrony with the wingbeat/muscle contractions.
• Motor is started by the fly jumping – second leg
(mesothoracic) – TDT (tergal depressor of the trochanter)
• muscles contract, with a delay, after being stretched (strainactivation) by the thorax being deformed by the opposing
muscle set
• delay in strain activation (with stiffness of the cuticle and
the drag on the wings – viscosity) determine the wing beat
frequency.
Where does strain activation
come from?
2 models:
1)
Geometry of the filament lattice (Wray)
2)
Crosslinks between thick and thin filaments.
Model 1:
Insect flight muscle has a very regular structure
compred to any other.
The spacing of the myosin heads and the actin
repeat are the same 38.5nm (note F-actin
repeat is normally 36.5nm).
Thus myosin heads and their binding sites have the
same spacing along the two sets of filaments
Insect flight muscle 
Image shows a thick filament rolled out flat (O = positions of myosin heads;
 = actin monomers that myosin heads can reach and bind to)
In the unstretched muscles the
‘offset’ prevents myosin heads
binding actin; applied stretch brings
them into register and they can bind.
Unstretched
Stretched
Model 2: That insect flight muscle-specific polypeptide extensions to
tropomyosin/troponins allow then to contact the thick filaments and
‘detect’ the relative movement of the two sets of filaments – no
evidence at all!
Vertebrate heart muscle is both calcium and stretch-activated (the
Starling effect) – believed this may be a direct effect of stretch on the
myosin in actomyosin crossbridge – strain affects myosin kinetics.