Download Cardiac muscle

9/27/16 – W5D1H4
Cell Physiology:Muscle Physiology
Why This Topic?
What would life be like without muscles? We would be trapped and unable to
move or even take a breath not to mind our hearts could not beat.
Understanding the basic physiological properties of muscle is important for
identifying clinical manifestations of various disease and pathological states.
Ionic disturbances, toxins, drugs, and congenital issues can all lead to changes
in muscle function which will be explored more in depth on W5D2H1-2.
Learning Objectives:
1. Explain the mechanism by which muscle contracts, outlining how the sliding of actin
filaments in sarcomeres is driven by ATP-dependent chemo-mechanical cycling of
myosin motor proteins.
2. Explain excitation-contraction (EC) coupling and relaxation in skeletal muscle by
identifying the roles of the t-tubules, the calcium channels (Cav1.1 [L-type] and
Ryanodine receptor [RyR]), the thin filament regulators (troponin and tropomyosin),
and the ATP-dependent SERCA pumps in these processes.
3. Understand the differences in EC coupling in skeletal, cardiac, and smooth muscle.
Describe the two- stage phospho-regulatory cascade that initiates contraction in smooth
muscle.
4. Compare the twitch contractions of slow/type 1 and fast/type 2 skeletal muscle fibers
and explain the molecular bases for the differences in twitch behavior.
5. Outline the shift in energy sources in a working skeletal muscle as it goes from rest to
extended periods of activity. Compare the energy needs in different muscle types.
6. Define muscle mechanics concepts including contractility, preload, afterload, isotonic
and isometric contractions. Compare the mechanics in different muscle types.
7. Explain how smooth, graded contractions of a skeletal muscle are produced by changes
in stimulus intensity and by the size principle of motor unit recruitment.
8. Contrast the innervation and location of single-unit vs. multi-unit smooth muscle types.
LO #1. Explain the mechanism by which muscle contracts,
outlining how the sliding of actin filaments in sarcomeres is
driven by ATP-dependent chemo-mechanical cycling of myosin
motor proteins.
Muscle terminology
1) skeletal muscle fibers
a. alpha motor neurons
b. neuromuscular junctions
c. motor endplates
d. motor unit
e. motor pool.
f. upper motor
g. lower motor
2) smooth & cardiac muscle
a. autonomic motor neurons
(postganglionic)
LO #1. Explain the mechanism by which
muscle contracts, outlining how the
sliding of actin filaments in sarcomeres is
driven by ATP-dependent chemomechanical cycling of myosin motor
proteins. (continued)
From organ to molecule
and back again
The “Thin” filament:
G actin and F actin (cytoskeletal microfilament)
The “Thick” Filament:
300 molecules of myosin II
LO #1. Explain the mechanism by which muscle contracts, outlining how the sliding of actin
filaments in sarcomeres is driven by ATP-dependent chemo-mechanical cycling of myosin
motor proteins. (continued)
During contraction, the thick and thin filaments slide past one another in this ratcheting
process, shortening the length of each sarcomere and consequently the length of the muscle
fiber. The sarcomere histology changes, i.e., I-bands will get shorter during contraction with
the increasing overlap between thick and thin filaments.
relaxed sarcomere
contracted sarcomere
From Karp, Cell & Molecular Biology
LO #1. Explain the mechanism by which muscle contracts, outlining how the sliding of actin
filaments in sarcomeres is driven by ATP-dependent chemo-mechanical cycling of myosin
motor proteins. (continued)
The classic
Length/Tension
curve for
skeletal muscle
Molecular Biology of the
Cell. 4th edition
Critical Point: No ATP leaves the muscle in a
state of rigor (a VERY brief period in a living
cell).
Critical Point: The binding of ATP decreases the
affinity of the binding and allows the myosin hea
to move in the next step.
Critical Point: The hydrolysis of ATP causes myos
to move (a.k.a. “cocking” of the head) into a hig
energy state.
Pi
Critical Point: A weak binding at this new
Critical
The
locationPoint:
caused
Pi release
release of Pi triggers the
power stroke.
Critical Point: Calcium MUST be present to
make binding of myosin to actin possible
and for this cycle to occur.
From your syllabus:
During muscle contraction:
a. The myosin heads (bound by ADP-Pi) bind to the actin filaments
b. Next, the myosin heads undergo a conformational change called a “power stroke”
to pull the thin filaments a short distance past the thick filament (ADP released)
c. Then the links between actin and myosin break (requires ATP)
d. Then the myosin head returns to its original conformation and the process is
repeated, as the muscle is contracting.
e. ATP is required to break the actin-myosin links to allow another power stroke.
LO #2. Explain excitation-contraction (EC) coupling and relaxation in skeletal muscle
by identifying the roles of the t-tubules, the calcium channels (Cav1.1 [L-type] and
Ryanodine receptor [RyR]), the thin filament regulators (troponin and tropomyosin),
and the ATP-dependent SERCA pumps in these processes.
1
2
3
4
6
Ryanodine
Ryanodine
receptor
receptor
SERCA
ATP
5
1. Somatic motor neuron releases ACh at
neuromuscular junction (1 impulse =
~60 vesicles of ACh)
2. End plate: Net entry of Na+ through
nACh receptor channel initiates first an
endplate potential (+30-40mV), and
then a muscle action potential is
produced when nearby voltage-gated
channels activated
3. Action potential travels deep into
muscle fiber along t-tubules. T-tubles
form triad with SR.
4. Voltage change in t-tubules triggers
conformational change in Ca2+
channels (DHP receptors & RyRs) to
increase intracellular Ca2+
5. Ca2+ binding to regulatory protein
troponin C in thin filaments which
displaces tropomyosin to expose
myosin binding sites on actin, allowing
contraction to begin & myosin binding
VIDEO
initiates the cross bridge cycle to
generate force.
6. See the SYLLABUS for more detail!!
LO #2. Explain excitation-contraction (EC) coupling and relaxation in skeletal muscle
by identifying the roles of the t-tubules, the calcium channels (Cav1.1 [L-type] and
Ryanodine receptor [RyR]), the thin filament regulators (troponin and tropomyosin),
and the ATP-dependent SERCA pumps in these processes.
Muscle Action potential (AP) generation ceases as ACh is broken
down by acetylcholinesterase (AChE)
The SR reabsorbs Ca2+ via SERCAs and the Ca2+ concentration in
the sarcoplasm decreases.
The Na + /Ca2+ exchanger extrudes Ca2+ from the sarcoplasm and
the Ca2+ concentration in the sarcoplasm decreases.
ATP is necessary for myosin to release from the actin; lack of ATP
will cause rigor
When Ca2+ approaches resting levels the troponin and tropomyosin
return to their resting positions. This change recovers the actin active
sites and prevents further cross-bridge formation
Without cross-bridge interactions, further sliding cannot take place
and the contraction ends
Muscle relaxation occurs, and the muscle returns passively to its
resting length
Animation of Muscle Contraction
Four minute animated review of muscle contraction
LO #3. Understand the differences in EC coupling in skeletal,
cardiac, and smooth muscle. Describe the two- stage phosphoregulatory cascade that initiates contraction in smooth muscle.
Cardiac muscle has similar EC coupling as skeletal muscle.
Some Important Differences:
1) Cardiac muscle has pacemaker cells that generate current;
current can pass between cells through gap junctions
2) Cardiac action potential is broad because of Ca2+ influx.
3) Diads not triads in cardiac
4) L-type Ca2+ channels are NOT coupled to ryanodine Ca2+ release
channels as they are in skeletal muscle. Cardiac muscle requires
Ca2+ induced Ca2+ release (CICR) from SR.
5) Different isoforms of troponin present in cardiac muscle
6) ANS controls the rate of contraction (parasympathetic &
sympathetic) and contractility (sympathetic only).
7) During recovery, most Ca2+ is recovered by the SR, but also
extruded by exchanger & Ca2+ pump
The source, spread, and conformation of the AP
in cardiac tissue (from your syllabus).
EC coupling in cardiac muscle from your syllabus: Please note that this diagram
“shows” a triad, but we’ll call it creative license to show both excitation and recovery on one
slide.
ANS control of cardiac Ca2+ levels in EC coupling
(quick review)
The ANS controls both the rate and force which cardiac muscle contracts.
Rate is controlled by both parasympathetic and sympathetic innervation of the SA
node, but contractility is regulated by the sympathetic nervous system.
Sympathetic postganglionic fibers synapse onto the cardiac myocytes and release
norepinephrine, which binds to 1 adrenergic receptors to create a signaling cascade
(G s) which leads to increase Ca2+ and contractility. Circulating epinephrine released
from the adrenal medulla has the same effect.
The ANS controls rate by modifying the rhythm of pacemaker cells. The pacemaker
potential is due to special properties of ion channels in nodal cells, the details of which
will be elucidated in the Circulatory systems block.
For now, understand that the parasympathetic vagus nerve innervates SA and AV nodes
to decrease rate through ACh muscarinic acetylcholine receptor M2 (G i) binding
which ultimately activates a K+ channel to hyperpolarize the cell.
Sympathetic nerves (preganglionic originates from T1-T5 level of the spinal cord)
innervate SA/AV nodes to increase rate through epi/norepinephrine binding of the 1
receptor which speeds up inactivation of the K+ channel and increases the opening probability of
Na+ and Ca2+ channels to depolarize the cell.
LO #3. Understand the differences in EC coupling in skeletal, cardiac,
and smooth muscle. Describe the two-stage phospho-regulatory
cascade that initiates contraction in smooth muscle.
Important points in smooth muscle EC coupling.
1.
Action potential (AP) / nervous system not required; all that is necessary is
increase in Ca2+ through a variety of mechanisms
2.
3.
Ca2+ influx in myocyte can lead to calcium-induced calcium release (CICR)
Ca2+ binds to calmodulin (CaM)
4.
Smooth muscle lacks troponin; for actin and myosin to interact, the light chain of
myosin must be activated by myosin light chain kinase (MLCK), which is
activated by CaM
5.
Active MLCK phosphorylates light chain myosin heads and increases myosin
ATPase activity
6.
Active myosin crossbridges slide across actin to create muscle tension (no
sarcomeres; cell contracts like “corkscrew”)
7.
Relaxation occurs when Ca2+ levels renormalize via Ca2+ ATPases & Na+/Ca2+ on
membrane, SERCAs
8.
Crossbridge cycling continues as long as ATP is present; relaxation is dependent
on myosin phosphatase, which dephosphorylates MLCK to deactivate it.
9.
Relaxation of smooth muscle in some vasculature can also occur through a nitric
oxide (NO)-mediated pathway
LO #4. Compare the twitch contractions of slow/type I and
fast/type II skeletal muscle fibers and explain the molecular bases
for the differences in twitch behavior.
Three types of skeletal muscle fibers: Type I (slow), Type
IIa (fast oxidative), and Type IIb (fast glycolytic). Fiber
types are defined based on: velocity, myosin ATPase
isoform, and biochemical profile.
LO #4. Compare the twitch contractions of slow/type 1 and fast/type 2 skeletal
muscle fibers and explain the molecular bases for the differences in twitch behavior.
 A twitch contraction is when tension is generated in a motor unit
in response to a single stimulus (like an AP).
 A twitch has three phases: latent, contraction & relaxation
periods
 Latent period is not variable, but contraction & relaxation are
determined by the fiber types in any given muscle.
Figure 18. Mean absolute power comparison between
Type I and IIa muscle fibers in female ~74 yr old
vastus lateralis muscles pre- and post- progressive
resistance training.
LO #5. Outline the shift in energy sources in a working skeletal
muscle as it goes from rest to extended periods of activity.
Compare the energy needs in different muscle types.
Four sources of energy (ATP):
1. Stored ATP (about 5 mmol/kg muscle; only about
3-5 s of max power before stores are depleted, but
they NEVER do get depleted!)
2. Phosphocreatine (about 25 to 30 mmol/kg
muscle; about 30 s max power until depleted)
3. Anaerobic glycolysis (peaks in as early as 30 s
but can result in [Lac]blood of 15-20 mmol/L).
4. Aerobic respiration (limited at the muscle by
mitochondrial capacity)
LO #5. Outline the shift in energy sources in a working skeletal
muscle as it goes from rest to extended periods of activity.
Compare the energy needs in different muscle types.
Byproducts
1.
2.
3.
Heat
CO2 and H2O
Lactic acid
Stores
1.
2.
Myoglobin stores O2
Glycogen – Primary source of glucose
Vmax for ATP production
1.
2.
CK reaction and myokinase reaction are the fastest
Anaerobic glycolysis is about 2.5x faster than aerobic pathway but
harvests only about 5% as much ATP per C6H12O6 and can’t use fat!
LO #5. Outline the shift in energy sources in a working skeletal muscle as it goes from
rest to extended periods of activity. Compare the energy needs in different muscle
types. (continued)
Energy sources and ATP utilization
1. Short high intensity activities like weight lifting or sprinting rely on ATP and
phosphocreatine stores. Burst-like activities like tennis rely on glycolysis and
respiration. Endurance activities depend on respiration using both glucose and
fatty acids. As long as a muscle has oxygen (and it always does unless blood
flow or PO2 is restricted) it will form ATP by aerobic pathways. But if the
exercise demands are great, the cells will resort to anaerobic pathways for ATP.
2. Energy sources for cardiac and smooth muscles are generally aerobic. The heart
primarily uses fatty acids (60-80 %) as energy sources. Limited anaerobic
pathways (2 % ATP derived from glycolysis) means that the heart requires high
amounts of O2 and if it becomes limited, irreversible hypoxic muscle damage
ensues (myocardial infarction).
3. Smooth muscle has slow ATPase activity so the ATP depletion is not usually an
issue.
LO #5. Outline the shift in energy sources in a working skeletal
muscle as it goes from rest to extended periods of activity.
Compare the energy needs in different muscle types. (continued)
1) Contractility is the ability to shorten forcibly when adequately stimulated.
2) Most skeletal muscles exhibit some amount of tension, or muscle tone
even if they are not consciously being contracted.
3) A muscle is typically stretched to some length (preload) such that the
overlap between actin filaments and myosin heads is optimized; too little or
too much preload will lead to less contraction in skeletal muscle because
fewer crossbridges can form. This is referred to as the length-tension
relationship.
4) Skeletal and Cardiac muscle have very different length-tension curves.
5) Innumerable crossbridge cycles occur during muscle contraction, but the
amount of force they generate is finite. The force resisting further
shortening after the muscle is stimulated to contract is called the afterload.
In skeletal muscle, the load is the weight of the object being moved. IN
cardiac muscle, afterload in mean arterial blood pressure.
LO #6. Define muscle mechanics concepts including contractility,
preload, afterload, isotonic and isometric contractions. Compare
the mechanics in different muscle types.
Two types of muscle contractions:
Isotonic: occur when a muscle shortens but maintains a constant tension – not common in
normal use.
Isometric: when the afterload is too heavy to lift and the muscle cannot shorten even though
crossbridge cycling continues to generate tension.
1.
2.
Cardiac muscle mechanics: Myocardial excitation always involves all fibers, and so all
fibers are involved in generating force as a unit. In cardiac, there is no option for
recruiting motor units, so if the force is to be changed, the ANS will regulate Ca2+
permeability.
1.
Contractility, preload, and afterload should wait until the cardiovascular class in the next
block! They are the major determinants of stroke volume!



Contractility considers the force of contraction at a given cell length and is changed by changes in
calcium availability.
Preload involves stretching the myocytes and is changed by ventricular filling.
Afterload involved the degree of pressure in the aorta which is affected by MAP.
Smooth muscle mechanics: Smooth muscle can contract rapidly, and then completely
relax, but in other cases, smooth muscle can maintain a low level of active tension for
long periods without cyclic contraction and relaxation.
LO #8: Explain how smooth, graded contractions of a skeletal
muscle are produced by changes in stimulus intensity (frequency)
and by the size principle of motor unit recruitment.
MUSCLE ACTIVITY VARIES!
How can more or less tension be generated?
 This is done through graded muscle responses.
In general muscle contraction can be graded in
two ways:
1. Temporal summation - changing the frequency of
stimulation by the alpha motor neuron
2. Spatial summation – changing the number of motor
units recruited (a.k.a. the size principle)
Temporal summation in muscle: Increased frequency of
stimulation generates more force; tetanus results when maximum
force is produced.
Spatial Summation of Motor Units
Motor units are recruited by size: as motor units with larger and larger muscle fibers ae
excited, contractile strength increases (size principle).
Size principle allows for force increases to occur in small steps.
Rarely are all motor units recruited; typically they are recruited asynchronously and “take
turns” to delay fatigue.
LO #8: Contrast the innervation and location of single-unit vs.
multi-unit smooth muscle types.
Smooth muscle has two main functional types:
1. Multiunit, tonic: Individual myocytes function independently and allows for fine control.
capable of maintaining sustained contractions. Found in e.g. large airways, ciliary & iris
muscle of eye, sphincters, vasculature, arrector pili (the small muscles that raise hairs,
and goose-bumps, on skin).
2. Visceral, phasic, single-unit, unitary: Gap junctions between neighboring cells allow for
current to spread across the muscle cells, so they act together as a syncytium. Some
smooth muscle cells contain pacemaker cells but autonomic neurons do synapse on a
few of the cells in the muscle to help regulate contraction. Phasic smooth muscle
contracts transiently when stimulated. Found in e.g. GI tract and urogenital walls
However, most smooth muscles are a blend of phasic and tonic, which allows them to
respond to a range of stimuli.
LO #8: Contrast the innervation and location of single-unit vs.
multi-unit smooth muscle types.