Muscle: Smooth muscle
Physiology
Week 11.1 (October 2020)
Outline
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What is smooth muscle
Different types of smooth muscle
Smooth muscle structure
Contraction
– Regulation of different forms of contraction
– Thick-filament regulation
– Latch state
• Regulation of Ca2+
– AP, hormones, neurotransmitters
• Hypertrophy and secretory function
Smooth muscle
• Smooth muscle is a non-striated muscle associated
with hollow organs and vessels
– Regulates flow, movement of material
• Functions with similar mechanisms to skeletal
muscle with some important differences
– Altered cellular organization
– Ca2+-activated force generation regulated by thick
filaments
– Contraction triggered by electrical signals and/or
hormone signals
– Can contract for extended periods of time
– Much greater complexity in regulation
Smooth muscle
• Two sub-types of smooth muscle
– Single unit
– Multi-unit
• Single unit smooth muscle are electrically coupled
via gap junctions
– Electrical stimulation of 1 cell activated other cells
– Wave of contraction – peristalsis (can be a pacemaker)
• Multi-unit smooth muscle not electrically coupled
• In reality there exists a spectrum of responses
– Locally produced activators or innervation can produce a
partially coordinated contraction
Smooth muscle
• Different types of contractile patterns
• Phasic smooth muscle exhibits rhythmic/intermittent
contractions
– Single unit smooth muscle
– E.g. in GI tract
• Tonic smooth muscle is continually contracted,
maintaining a level of ‘tone’
– Multi-unit smooth muscle
– E.g. respiratory or vascular smooth muscle
– Continuous activation not associated with AP
generation/propagation
Smooth muscle
• Different types of contractile patterns
Smooth muscle cells
• Smooth muscle forms layers around the vessel or organ
– Arranged circumferentially for blood vessels, airways – aid
contraction/dilation of vessel, fluid flow
– Circumferentially and longitudinally for GI tract – aid in mixing and
propelling contents, organ volume
• Layers contain innervations (autonomic nerves)
• Additional elements (epithelial tissue, connective tissue)
separates muscle from contents
Blood vessel (arteriole)
Intestine (*neuron)
Smooth muscle cell contacts
• Cell-cell contacts allow mechanical (and electrical)
communication between cells
– Similar to cardiac muscle
– Given arrangement, must activate simultaneously and be
mechanically linked (otherwise contraction would be
balanced by stretch and no net action)
• Gap junctions coordinate AP prorogation (and small
molecules such as IP3)
• Adherin junction provide mechanical linkage
Smooth muscle cell structure
• Different structure to skeletal and cardiac muscle
– 50-500um long, 2-10um diameter
• Lack T-tubules,
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Instead rows of inward pockets (caveola)
Still close association between PM and SR
Caveola site of many Ca2+ handling proteins (CaV, NCX)
SR network still present
• Contractile apparatus organized differently within
cell
– Still consists of thick and thin filaments that interact
– Regulated by Ca2+ (CaV, RyR, SERCA, IP3R)
Smooth muscle cell structure
• Thick (myosin) and thin (actin)
filaments are present in smooth
muscle, as in skeletal/cardiac
muscle
– Not in transverse alignment to the
cell: no striations
– Still organized in contractile units
– Thin filaments made up of actin (no
troponinC)
– Thick filaments made up of myosin
(different genes)
• Also aligned in small bundles: 3-5
thick filaments surrounded by thin
filaments
Smooth muscle cell structure
• Groups of thick and thin
filaments are connected to
dense bodies
• Dense bodies
– contain alpha-actinin
– Equivalent to sarcomere, z-line
– Point at which force is transmitted
form thick/thin filaments
• Intermediate filaments link
dense bodies into cytoskeleton
(desmin, vimentin
Smooth muscle contraction
• Several factors can control smooth muscle contraction via
altering Ca2+ levels (not just an AP propagation)
– APs are highly variable and not always needed
• Can have slow twitch, summated (tetany) or rhythmic APs
– Characteristic of single unit smooth muscle
Smooth muscle contraction
• Several factors can control smooth muscle contraction via
altering Ca2+ levels (not just an AP propagation)
– APs are highly variable and not always needed
• Non-AP or non Vm dependent changes in contraction
– Small changes in Vm can inhibit CaV channels and Ca2+ influx
– Graded changes, characteristic of multi-unit smooth muscle
– Can act via IP3R, cGMP, cAMP, or other signaling
Smooth muscle innervation
• Smooth muscle can be innervated by the autonomic nerves
– Sympathetic fibers innervate arteries, sympathetic and
parasympathetic fibers innervate other tissues
– Neuromuscular junction less complex than skeletal muscle:
varicosities are swollen regions of neurotransmitters
• Activity can also be triggered by hormones
Smooth muscle
acting like skeletal
muscle
Smooth muscle
acting like cardiac
muscle
Regulation of contraction
• Molecular mechanisms of contraction distinct to skeletal,
cardia muscle
• Requires phosphorylation of myosin light chain
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In response to elevated Ca2+
Ca2+ binds calmodulin
Ca2+-calmodulin activated myosin light-chain kinase (MLCK)
MLCK phosphorylates myosin light chain
Allows cross-bridge cycling (critical step)
‘Thick-filament regulated’ due to different myosin gene products
• Cross bridge cycling similar to skeletal and cardiac muscle
– After binding, myosin conformational change pulls actin fibre and
force generation (ratchet action )
– ADP, P release, ATP binds
– Myosin unbinds, conformational change ready for another cycle
Regulation of contraction
• Cross-bridge cycling
continues as long as MLC is
phosphorylated (Ca2+
elevated)
– After binding, myosin
conformational change pulls
actin fibre and force
generation (ratchet action )
– ADP, P released, ATP binds
– Myosin unbinds,
conformational change ready
for another cycle
• Low Ca2+, MLCK inactive,
MP dephosphorylated MLC
Regulation of contraction
• Ca2+ required for
contraction, sensitivity
varies
• Several hormones can
increase force of
contraction at sub-maximal
Ca2+
• E.g. inhibition of MP via
activation of G12/13 GPCR
(acts via GEFs) by
catacholamines,
vasopressin, angiotensin
Phasic/Tonic Contraction
• Phasic contraction: Ca2+ MLC-P, force generation peaks and
returns to baseline
• Tonic contraction: Ca2+ MLC-P peak then decline to a
residual level above baseline
– Force slowly increases to sustained level
– Sustained force uses only subset of cross bridges
– Reduced ATP usage – ‘latch state’
Phasic/Tonic Contraction
• In the latch state contractile force is maintained with low ATP
expenditure
– Reflects dephosphorylation of MLC
• When MLC phosphorylated, cross bridge cycling relatively
rapid (for duration of elevated Ca2+)
• If attached cross bridge is dephosphorylated by MP, cross
bridge cycling decreased
– Rate of detachment slower, cycle awaits rephosphorylation
• For low Ca2+: rate of cross bridge dephosphorylaiton
increases, period in attached force generating confirmation
increases
– Low rate of Ca2+-dependent MLCK essential, otherwise relaxation
• ~300 fold less ATP used in this state
– No fatigue unless O2 reduced for oxidative metabolism
Regulation of Ca2+
• Two sources of Ca2+: Sarcolemma (PM) influx, Sarcoplasmic
reticulum
• SR: Release triggered by IP3R activation by Gq GPCRs
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Many hormones or neurotransmitters capable
Graded effect in level of Ca2+ released
Sympathetic fibers, angiotensin, vasopressin,
ACE inhibitors block angiotensin production to promote vasodilation
• SERCA refills SR
• RyR also expressed (Ca2+-activated Ca2+ channel on SR)
– Don’t act in similar manner to skeletal, cardiac muscle
– Spontaneous activity produces Ca2+ sparks
– Ca2+ accumulation hyperpolarized KCa channels
Regulation of Ca2+
• PM: CaV (L-type) allow Ca2+ influx
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Channel activation forms upstroke of AP (as in beta cells)
SR depletion activates Ca2+ influx (unknown mechanism)
Extracellular Ca2+ required for sustained contraction
CaV blockers or K+ channel activators reduce contraction, and visaversa
• NCX (Na+-Ca2+ exchanger) extrudes Ca2+ form cell
– Competes with SERCA
Regulation of Ca2+
• Hormones and drugs that regulate cAMP and cGMP relax
smooth muscle
• cGMP can be elevated by NO production by nerves,
vascular endothelial cells
– Or ANP receptor activation
– Complex signaling: activation of MP or Ca2+ pumps
• cAMP can be elevated by beta-adrenergic receptor
activation
– Attenuate Ca2+-dependent increase in MLCK activity
– Reduce Ca2+ influx by increasing Ca2+ sparks
– Vasodilation in working muscle due to production of adenosine,
purinergic receptor activation and cAMP action
Regulation of Ca2+
Hypertrophy
• Number of cells increases during development
(hyperplasia)
• Tissue mass increases under sustained work
• E.g. in media of artery in hypertension
– Due to mechanical load on muscle cells
– Polyploid cells: increased synthesis of contractile proteins
• E.g. uterus lining as birth approaches
– Increased mass and gap junction expression
Secretory function
• Smooth muscle cells are capable of secreting
factors that make up the extra-cellular matrix
– Collagen, elastin, proteoglycans
• When isolated and cultured, lose contractile
machinery, expand rough ER and golgi
– Proliferate, deposit EC matrix
– Reversible upon cessation of proliferation
• Processes poorly understood
– Mechanical load, hormones and growth factors linked
– Similar process occurs in athlesclorosis
– Vessel wall damage induces smooth muscle changes
and contribution to plaque formation
Length Tension Relations (Smooth)
• Smooth muscle shows similar Length-tension relations
compared to skeletal muscle
– Force shows a Bell-shaped curve
– Smooth muscle cells can shorten more
• Smooth muscle is generally only partially active
– Peak force varies with stimulus
– Skeletal muscle where an AP always generates a full ‘twitch force’
• Active force comparable to skeletal muscle
– Fewer fibers, but more likely to be attached given slow cycling
Length Tension Relations (Smooth)
• Smooth muscle can shift the length-tension curve
– Length adaptation
• If stretched, L0 shifts to longer lengths
– If contracts, L0 shifts to shorter lengths
– Shift occurs over minutes-hours
– Possible remodeling to change number of contractile units
Force-Velocity Relations
• During contraction, the velocity of contraction is related to
the amount of force required
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In the absence of load velocity is maximal
Maximal velocity (V0) due to maximal cycling rates of cross bridges
Maximal ATPase activity
V0 higher for fast-twitch skeletal muscle
Force-Velocity Relations (Skeletal)
• V0 higher for fast-twitch skeletal muscle
– Maximal ATPase activity
• Increasing load reduces velocity of contraction
– At velocity = 0, maximum load achieved (no contraction possible)
– Further load stretches muscle (negative velocity)
• Maximum load related to number of active cross bridges
– Greater for fast-twitch muscle (larger diameter fibres)
– Tetany
• Work done is related to power generated at each load (rate
of work done)
– Velocity x load applied
– Maximal work at sub-maximal load
Force-Velocity Relations (Smooth)
• Smooth muscle shows similar decreases is velocity with load
• Much lower V0
– Decreased myosin ATPase activity
Force-Velocity Relations (Smooth)
• Skeletal muscle force-velocity
curve only determined by
load and myosin isoform (fast
vs slow twitch)
• Smooth muscle velocity and
force vary
– Reflect number cross bridges
and cycling rate respectively
– Dependent on myosin
phosphorylation (Ca2+
dependent)
Force-Velocity Relations (Smooth)
• Increased myosin
phosphorylation increases
both maximum velocity and
maximum load
• More myosin phosphorylation
means more actin-myosin
interactions and thus more
force generated
• More myosin phosphorylation
means greater rate of
detachment and greater
cycling (reducing the latch
state)
Summary
• Smooth muscle controls flow and movement of material in
vessels and hollow organs
• Smoot muscle has different contractile patterns
– Phasic and tonic
– Single unit and multi-unit
• Smooth muscle has similar contractile apparatus
– Non-striated, organized around dense bodies
– Thick filament regulated
– Calcium dependent contraction
• Calcium levels regulated by SR and PM
– Action potentials, neurotransmitters, hormones, locally released
factors
• Hypertrophy occurs in response to mechanical load
– Secretory function linked to atherosclerosis, poorly understood