PSIO 303B EXAM III STUDY

GUIDE:
InCLUDES LECTURE

Lecture XXXII
Introduction to Block III
Basically, this is a simple section on how the heart cell fails. This will introduce the heart cells physiology
through the case study of a disease that is well-known to many, particularly congestive heart failure. This
is where normal heart function eventually transitions into severe heart dysfunction. This block will gather
understanding of:
1. Anatomy of the Heart Cell
2. Physiology of Cardiac Muscle Contraction
3. Intracellular Signaling in Heart Cells
4. Congestive Heart Failure when things go bad
The recurring themes in this course is simply the following:
1. Cellular Organization: Molecule Cell Complex Tissue
2. Cellular Specialization: Development Divergence
3. Cellular Structure and Function: Generic Cell Cardiac Cell
4. Cellular Homeostasis: The reversible transition from normal to abnormal (Normal Abnormal)
5. Cellular Failure: Cell Failure Whole Heart Failure
Understanding the Heart is based on the following:
1. Model System: Using a simulation to solve non-model problems, such as in heart failure.
2. Non-Intuitive: Use of research and facts to deduce the answer.
3. Empirical Data: Data produced from observation and experiments.
4. Cant Get Enough: Well, that..sounds..like an addiction?
With this we can organize this into the several recurring themes:
1. Cellular Organization: Chemical, Cellular, Tissue, Organs, Organ Systems, Organism
2. Cellular Specialization: From a generic cell to a rod cell, but can also entail the development of a
cell to blood vessels or the muscular heart. The specialized cell can have a specific function.
Cardiac cell specialization has the following properties: (1) contractile, (2) conservation, (3)
electrical, (4) energetic, (5) intrinsic, and (6) extrinsic.
3. Cellular Structure and Function: Understanding cellular structure and function involves knowing
about the various roles of the cells and organs of the organ system. For example the speed of
contraction correlates with the ATPase activity of myosin. This property can arise from its
components: (1) striated pattern, (2) sarcomeres, (3) myofilaments, (4) T-tubules, (5)
sarcoplasmic reticulum, (6) Z-disk, and (7) mitochondria. These components play a role in
adaptation of the cardiac cell.
4. Cellular Homeostasis: Cardiac cells exhibit various forms of regulation, through (1) negative
feedback and positive feedback which are (2) acute or long-term. They can be (3) physiological
or pathological, exhibiting (4) extrinsic or intrinsic properties. They can arise from (5) non-genetic
or genetic causes, which then spurs the goal or either reaching (6) homeostasis or steady-state.
This will play a major role in adaptation. Homeostasis is the relative constancy of the internal
environment.
5. Cellular Failure: This can arise from the failure of homeostasis, which are attributed to the
previously stated causes.

Lecture XXXIII
Case Study: Congestive Heart Failure
Distinguish between CHF as syndrome compared to a disease.
Congestive heart failure (CHF) can be defined in two different manners: as a (1) syndrome, and as a (2)
disease. Generally, it is referred to the inability of the heart to supply sufficient blood flow to meet the
needs of the body, causing shortness of breath, leg swelling, and
exercise intolerance. Congestive Heart Failure can be considered a
syndrome mainly because the kidneys can maintain a salt-avid state.
However, other organs can contribute to its progressive nature, such
as the failure of the liver.
The disease aspect involves the failure of the cardiac cell. An initial
insult (genetic or non-genetic) can cause a production of factors
(cellular signaling) and changes in the gene profile and heart
remodeling (cellular remodeling) which expands to the level of the
organ (organ remodeling). Eventually, there will be regulation (feedback control) and will be (in a longerterm) will be of concern as the body attempts to reset itself. This begins a downward spiral with
maladaptation, due to remodeling and eventual ventricular dysfunction.
All in all, this can be diagnosed in the clinic as well as in the hospital setting. A patient typically enters the
clinic or hospital and the physician will identify structural or functional abnormalities with a (1) full history
and physical examination, (2) non-invasive imaging and functional analysis, (3) invasive imaging or
functional analysis, and (4) laboratory parameters.
A full history and physical examination takes into account the initial complaint (not the main complaint),
symptoms in context or normal activities, and obvious physical signs. The main ones in consideration in
the physical examination are: (1) reduction in effort tolerance, (2) syndrome of fluid retention, such as
edema, and/or (3) no symptoms of cardiac disorder.
Abnormal
Normal
Noninvasive imaging will involve the use of imaging tools
such as echocardiography, magnetic resonance imaging,
Transesophageal Echocardiography
and ultrasound. This can allow a general idea of function
parameters and a better idea of what to fix.
Echocardiography along a single dimension can allow understanding of the
diameter of the chamber size in contraction (systole) and relaxation (diastole).
Noninvasive imaging can allow understanding of two variables: (1) fractional
shortening and (2) ejection fraction. Fractional shortening is the change in the
diameter in systole and diastole. Ejection fraction is the volumeRightheartcatheteriza9onisusedtomeasurepressures,sampleoxygenconcentra9ons,
ejected in every
anddeterminethefunc9onalcapabili9esoftheheartchambers.
single beat. These variables allow functional characterization of the
heart.
Luedde M et al. Cardiovasc Res 2010

Invasive imaging techniques can be done to further define the extent of the
diagnosis. Tools often include the transesophageal echocardiography and
right heart catheterization. There has been no established role in
periodic invasive or noninvasive hemodynamic measurements in the
LVEDPpreload
management of heart failure. The tranesophageal echocardiography
involves insertion of an imaging probe into the esophagus, giving it a
direct view of the heart. The image, though, can be perturbed by obesity.
Right heart catheterization involves insertion of the probe into the blood
vessels and attaining measurements. It2 is used to measure pressures,
sample oxygen concentrations, and determine the functional capabilities
of the heart chambers. It is a good assessment of the functional
parameters, because it can show true pressure measures in the
chambers of the heart.
Other confirmations can involve laboratory testing, particularly for serum electrolytes, serum brain
natriuretic peptide, and other tests for renal function. This confirms the multisystemic considerations in
congestive heart failure. The heart wont completely give out, but the kidney or the liver will. From these
factors we can help determine a mode of treatment suitable for the patient.
Treatment modalities and course of patient care are in the form of (1) pharmacological, (2) surgical, and (3)
transplant efforts. Most drugs utilized for the treatment of heart failure are prescribed on the basis of their
ability to improve symptoms or survival rather than their effect on hemodynamic variables. There are

several different stages, according to the New York Heart Stages

Association,
of heart failure, with recommended
in the Development of Heart Failure/Recommended Therapy by Stage
therapy based on each stage.
Class I: Patients with cardiac disease but
without resulting limitation of physical activity.
Ordinary physical activity does not cause
undue fatigue, palpitation, dyspnea, or anginal
pain.

No
objective
evidence
of
cardiovascular disease
Class II: Patients with cardiac disase resulting
in slight limitation of physical activity. They
are comfortable at rest. Ordinary physical
activity results in fatigue, palpitation, dyspnea,
or anginal pain. Objective evidence of
minimal cardiovascular disease.
Class III: Patients with cardiac disease
resulting in marked limitation of physical
activity. They are comfortable at rest. Less
than
ordinary
activity
causes
fatigue,
palpitation, dyspnea, or anginal pain. Objective evidence of moderately severe cardiovascular
Jessup et al 2009 (119) GuidelineFocused Updateon Heart Failure
disease.
Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity
without discomfort. Symptoms of heart failure or the angina syndrome may be present even at
rest. If any physical activity is undertaken, discomfort is increased. Objective evidence of
severe cardiovascular disease.
Copyright 2009 American Heart Association

Prognosis can often be predicted by with computer programs, but therapy is ultimately going to be focused
on improving prognosis if not stabilizing the patient.

List at least three causes for CHF.

There are several causes for congestive heart failure, on a pathological aspect:
1. Hypertension: high blood pressure can impede blood flow to the heart
2. Myocardial Infarction and Atherosclerosis: Blockage to specific parts of the heart can causes
coronary events and damage to the myocardium.
3. Diabetes/Obesity: Elements of the metabolic syndrome can increase the risk for heart attack or
disease.
4. Viral Myocarditis: Viral infection to the myocardium can perturb function by causing a reduction to
an abnormal state.

Define cardiac remodeling.

Cardiac remodeling refers to the histological and structural changes in size, shape, and eventual function
of the heart after injury. They can be attributed to anything to can perturb function along the
cardiovascular system, such as changes in pressure and volume as well as injury.

Identify cause of
Cardiomyopathy.

Familial

Hypertrophic

Cardiomyopathy/Hypertrophic
Familial Hypertrophic Cardiomyopathy is
typically caused by mutation in one of the
genes
known
to
encode
different
components
of
the
sarcomere,
characterized
by
left
ventricular
hypertrophy in the absence of predisposing
cardiovascular conditions.
It can be
manifested in the form of progressive heart
failure to sudden cardiac death with
variation among each individual. Changes
in the following genes and expressed
proteins can play a role in hypertrophic
cardiomyopathy.

The mutationPheidippides,ayounglongdistancemessenger(c.490BC)
of particular interest in this block will be a mutation in myosin S1. Mutations have been
pointed out throughout the myosin head and cause a long-term progression. Perturbations do not imply
decrease in function. They can often enhance function but eventually cause later hypertrophy and
dilation. One study observed the relationship of gender to overall hypertrophic cardiomyopathy (HCM)-

related mortality and progression to New York Heart Association (NYHA) functional classes III and IV, or
heart failure (HF) or stroke death (right panel). In general, women with hypertrophic cardiomyopathy were
under-represented, older, and more symptomatic than men with a higher risk of progression.

Lecture XXXIV
Cardiac Muscle Structure and Ultrastructure
Identify the 4 chambers of the heart.
The four chambers of the heart is as follows: the (1) right
atrium, (2) right ventricle, (3) left atrium, and (4) the left
ventricle. An atrium is the chamber of the heart that
receives blood, either from the systemic circulation (as in
the right atrium) or the pulmonary circulation (as in the left
atrium). The ventricles are mainly the pumping muscle of
the heart, responsible for the ejection of blood either to the
lungs (as in the right ventricle) or to the systemic
circulation (as in the left ventricle). The left ventricle is
much larger in size in comparison to the right ventricle due
to its function of pumping a large volume to the bodys
system. The two ventricles are separated by the interventricular septum, further enforcing a closed
circulation. The left ventricle is typically of interest because any remodeling that decreases the size of the
left ventricles wall can consequently decrease the function of the ventricle.
Short axis section of the heart.

Understanding orientation. If there is a picture.

Trace the path of blood through the heart and throughout the body.
The best way to illustrate a path of blood through the heart and through the body is through a flow chart,
which follows this statement:
Systemic
Systemic
Circulation
Circulation

Superior/Inf
Superior/Inf
erior
erior Vena
Vena
Cava
Cava

Right
Right
Atrium
Atrium

Aorta
Aorta

Right
Right
Ventricle
Ventricle

Left
Left
Ventricle
Ventricle

Pulmonary
Pulmonary
Arteries
Arteries

Left
Atrium
Left Atrium

Lungs
Lungs
Pulmonary
Pulmonary
Veins
Veins

List the 3 components of ventricular remodeling/adaptation.

Ventricular remodeling is deifned in a particular sequence of events. Physicians and scientists monitor the
progression of disease from the initial insult (acutely) to the long-term (chronically). As part of that
progression of disease, there are changes in the structure of the heart, starting with the ultrastructure.
Under hypertensive conditions, it grows in a different way relative to exercise conditions. With the cellular
modeling, there will be systemic remodeling. The heart resets itself at every moment of the human life,
changing constantly in response to external or internal stimuli. The genetic mutation in familial
hypertrophic cardiomyopathy will be the initial insult under study in this block.
Disease progression is characterized by adaptation and remodeling. Remodeling refers to the changes in
size, shape, and function of the heart after insult to the ventricles. There are three parts of this remodeling
that spiral towards the disease state:
1. Cellular/Biochemical: Within that cell, there is chemical signaling occurring and the heart will
remodel by signaling. It will change in certain aspects.
2. Ultrastructural/Histological: Observing the fact that there is going to be a structure change in the
heart. The ultrastructure and histology are altered. Along with the cellular remodeling, you get
structural remodeling.
3. Genetic/Molecular: Cellular signaling will affect gene expression. As the disease progresses, some
are activated while others are deactivated. Ultimately, there will be changes in the molecular

level. Cellular signals will impact cell in terms of gene expression, which feed back into the
Earlystagesofheartdevelopment
cellular/biochemical signals.
During this initial stages, this is occurring at a rapid pace. This remodeling in the context of development is occurring at a rapid pace.

Denition of heart elds.

Initially, remodeling is occurring at a rapid pace in the early stages of heart

development, and continue to remodel until the end of life. In the early
stages, the bilateral heart fields form after progenitor cells have migrated
from the primitive streak (shown as A1). Fusion of the bilateral heart fields
at the midline creates a cardiac crescent (A2). Fusion of the cardiac
crescent leads to the formation of the
B:ThetubularheartatthestagedepictedinA3
C:AJ
A1:Bilateralheartfied
A2:Fusionofthebilateralheartfie
A3:Fusionofthecardiaccrescentleadstothe
A4:Disintegra'
erdisintegra'
onofthedorsalmesocardium
l onofthedorsal
sf ormaJ erprogenitor
dsatthe
linear heart tube (A3). Disintegration of
issuspendedfromtherestoftheembryoby
mesocardiuminthemidsec'
cellshavemigratedfromtheprimi'
midlinecreatesacardiaccrescent.
forma'
enablesthehearttubetoundergoits
onofthelinearhearttube.
on,theheart
vestreak.
thedorsalmesocardium
tuberemainsaPachedtotheembryoby
characteris' cDloop.
the dorsal mesocardim enables the heart
meansofitsdorsalmesocardialconnec' onsat
thearterialandvenouspoles.
tube to undergo its characteristic D-loop
(A4).
The tubular heart at A3 is
suspended from the rest of the embryo by the dorsal mesocardium (B).
After disintegration of the dorsal mesocardium in the mid-section, the
heart tube remains attached to the embryo by means of its dorsal
mesocardial connections at the arterial and venous poles (C). By
embryonic day (E) 8.5-9 in a mouse, the respective components of the
embryonic heart still aligned in series (D).
Looping to yield
primordial heart.

Convergence

There is a rapid and robust modeling.

We can study development early on in very early

organ systems.

Tortora book.

Remodeling is occurring at a rapid pace.

Snarr et al. DEVELOPMENTAL DYNAMICS. 237:28042819, 2008

Heart reaches a point to where the fetus is born, there is physiologic growth.

In the human, the heart continues to develop to the point where the fetus is born, and consequently spurs
physiological growth.
If you look at the heart, the bers are somewhat spiring from the apex up to the base.
The bers are starting to swirl from the apical point.

Differentiate between fiber orientations

endocardium compared to the epicardium.

in

the

The heart has a very specific orientation, which differs based on body
size. In the context of disease, the heart will growth, and the heart will
If you lok at the bers, there is a different orientation. This is actually orientation. This is ber orientation from the epicardium
be of different
size because the body is pumping a different volume.
and fan out towards the midwall and then fan out towards the enocardium.
Understanding orientation is an important thing in diagnosing the
has signicance: allows to have a wringing motion and pack down more effectively. The heart cell is sitting there and just in a
patient.Itspecic
It position.
is important to first understand that the heart has certain
ultrastructures. One of them is the pericardium. The
pericardium will have a dramatic impact due to its
pericardial fluid. The fluid reduces friction of the heart. The
myocardium has a strong distinction from the pericardium
and endocardium, and there are specific orientations of
these fibers in order to allow the heart to function better.
Observing the heart, one can note that the fibers are
spiraling from the apex up to the base. They are starting to
swirl from the apical point. This allows contraction to
contract blood, wringing out the entire blood volume from
the chamber.
The fiber orientation shows that the
endocardium fans out but decreases in the spread as it
approaches the midwal. However, what is also of interest is
that as one approaches the epicardium, there is also
fanning out in the opposite direction. Once again this is
significant to allow a wringing motion of the heart with more
effective packing. There is regional variation in these
cavities, and the fiber orientation plays a role in its
contractility and this is the significant variable that is
diminished in disease states. If fiber orientation is disrupted, there may be significant pumping action.
Spirals outwars as well.

Heart contracts in a spiral orientation and allow contraction to contract blood. Heart has the ber orientation
to wring out blood from the chamber volume.

Orientation is a real critical factor!

Heart is made of myocytes.

What that means, the 20%
D o If
w you
n l o a look
d e d f at
r o the
m c number
i r c r e s . a hof
a j cells
o u r n ain
l s .the
o r g heart.
a t U n iThe
v e r s majority
i t y o f A r of
i z o the
n a ocells
n M are
a r c hnon-myocytes.
2 3 , 2 0 1 0
(myocytes)
are the ones with myosin and actin. The volume of the heart is the 25% myocytes. Most of the weight of the heart is the myocytes.
Fibroblasts, for example, are non-myocytes. Most of the non-myocytes and broblasts. THey play a role in not only collagen but also in signaling.
It is an amorphoous structure. Fibroblasts can respond to external signals as well. Production of collagen is done by broblasts.

List the major non-myocyte cell type and describe its function.

In the rough endoplasmic reticulum is where the ribosomes are located. THe collagen is being assembled and put together.
Preprocollagen --> Procollagen (N-terminal removal) --> Hydroxylation of Proline and Lysines --> Glycosylation of
Lysines --> Protein Disulde Isomerase--> Triple helix formation --> Movement to Golgi for Secretion --> proteolytic
cleavage (outside cell) --> Covalent cross-linking --> 3D STRUCTURE

Pollard and Earnshaw Fig 29-4

The heart of course, is made of myocyes. However, if you

look at the populations of cells in the heart, the majority
actually consists of cells known as non-myocytes. What that
Fibroblasts main role is to
produce means is that myocytes are the contracting factor, and are
collagen.
the majority of the volume (meaning that most of the weight
of the heart is the myocytes). Fibroblasts are one example
of a non-myocyte. Most of the non-myocytes are fibroblasts.
They play a role in not only collagen but also in signaling. It
is an amorphous structure, and can respond to external
signals as well. Their major function is the production of
collagen.

2005 Elsevier

Collagen is produced in the rough endoplasmic reticulum, where the ribosomes are located. It is
assembled in the following manner:
1. Preprocollagen
2. Procollagen (N-terminal removal)
3. Hydroxylation of Prolines and Lysines
4. Glycosylation of Lysines
5. Protein Disulfide Isomerase Enzyme that allows proper orientation towards the structural
integrity path. It will target specific amino acids and allow formation of the triple helix in a
specific manner.
6. Triple Helix Formation
7. Movement of Golgi for Secretion
8. Proteolytic Cleavage (outside the cell). The protein
is claved.
9. Covalent Cross-linking: Main element of covalent
modification.
10. 3D structure
Once outside the cell, it becomes cleaved.

Protein Disulde Isomerase is enzyme that allows proper orientation towards the structural integrity path. It will target specic amino acids and allow formation of
the
triple-helix in a specic way.
COVALENT MODIFICATION = CROSSLINKING

Covalent modication is catalyzed by lysyl oxidase. Important event that occurs during the development of
disease,
especially if the heart is going to increase in size.

Covalent modification is catalyzed by lysyl oxidase. Lysyl

oxidase catalyzes the formation of covalent bonds between
the ends of collagen molecules.

Lysyl oxidase catalyzes the formation of covalent bonds between the ends of collagen molecules.

Pollard and Earnshaw Fig 29-6

2005 Elsevier

Describe the function of the extracellular matrix in the heart and how it
relates to collagen.
The extracellular matrix in the heart has several functions:
1. Provision of structural integrity: It is one of the more important structural components. An
individual heart cell can be torn apart. However, the whole heart cannot be torn apart because of
collagen.
2. Maintenance in the alignment of myofibrils: It plays a role in how the structure is laid down
initially. It is known that having the matrix allows myofibrils to sit in a very specific orientation. In
short, the extracellular matrix dictates orientation.
3. Reservoir for bioactive molecules/signaling components: Signaling is occurring between the
myocardial cells and the extracellular matrix. The cells that make matrix proteins are high in
number, and have an important role in signaling. There is this autocrine effect that is attained
from the dictation of cellular processes.
4. Maintenance in the structural interaction with the vascular system: It has to feed itself. The
extracellular matrix has a role in maintaining the interaction with the vascular system. It keeps
the vessels in this region. The role of the matrix is not just to provide a framework for the heart
cell, but designate where different
FIG. 1. Myocardial hydroxyproline content, reflective of fibrillar collagen content, initially
fell from reference control values following isoproterenol-induced myocardial infarction
components go.
(MI) as shown by the open arrow
By monitoring the hydroxyproline content, we can determine the extent of heart damage.

Now this begs the question as to the relevance of

collagen. There are a number of vessels that
have a network of proteins. It is made of these
collagen fibers. The matrix is consists of several
different components, but the major one is
collagen fibers. It is used structurally throughout
the body. If they are put in a specific orientation,
they are extremely rigid and have a lot of
structural integrity. Each of these fibers are in the
triple helix. As they form the triple helix, the
structure becomes remarkably stable.
It is
extremely versatile and can be used for different
components.
There are different types of
Spinale, F. G. Physiol. Rev. 87: 1285-1342 2007
collagen fibers in the heart, and distributed
throughout the body. In the heart, though, the predominant collagen fibers are Type I and Type III. The
ratio of these fibers is associated with disease progression. An increase in Type III is associated with
disease states, and observations in the transition from Type I to Type III can allow inferences on disease
progression. This can also allow the inference that a transition from a normal to disease state in cells will
allow inference of the abnormal ultrastructure of the heart.
As the heart is building,
you
are breaking down collagen.

Rapid production of collagen

thus increase in hydroxyproline.

Lysyl oxidation can infer

Copyright 2007 American Physiological Society

Two proteins that are abnormal are fibrin and laminin. Fibronectin is a glycoprotein of the extracellular
matrix that binds to receptor proteins called integrins, and also plays a role in the binding of extracellular
matrix components such as collagen and fibrin. Its peptide structure consists of certain domains and areas
which can bind to the cell. If there is a genetic abnormality, you can have a gene that can make multiple
proteins, and muscle has many different types of myosin. Each chain is almost 2,500 amino acid residues
and each chain is folded into five or six rodlike domains connected by flexible polypeptide segments. The

Interacts at the C-terminus. It has specic amino acid sequence that can interact with the cell.
When that bronectin molecule interacts with that cell, they have interaction through a receptor.
It can allow a signaling pathway to occur.

individual domains are specialized for binding to a particular

molecule or to a cell. Fibronectin interacts at the C-terminus,
and has a specific amino acid sequence that can interact with
the cell. When that fibronectin molecule interacts with that
cell, they have interaction through a receptor and allow a
signaling pathway to occur.
Laminin --> Another protein that can multiple
interacting
sites. Can interact with molecules and tethering.
Can alter the way the matrix is growing.

interacting sites. Laminins are trimeric

secreted and incorporated into cellextracellular matrices. It is vital in the
survival of tissues, and defects in
poor muscular development. From there,
laminins can alter the pathway of the
extracellular matrix. It is multidomain
composed of three polypeptides (A , B1,
disulfide bonded into an asymmetric
Three types of chains, three types of B1,
chains have been identified to allow
18 different laminin isoforms.

If something goes wrong, you can have

a breakdown in the
matrix.
Matrix has a critical role in structure and signaling.

Laminin is another
protein
that
can
have
multiple
proteins that are
associated
maintenance
and
laminins can cause
you can infer that
development of the
glycoprotein that is
and B2) that are
crosslike structure.
and two types of B2
association to form

As a whole, there are collagen molecules that are interacting with laminin molecules, and they can
combine to form a rigid matrix, with structure and orientation. This rigid structure is produced and rapidly
modified during a severe disease stimulus, and remodeling that occurs at the matrix level is rapid. There
are a number of proteins involved in the regulation of this organization, but the main ones of concern are
fibronectin and laminin.

Lecture XXXV
Cardiac Muscle Structure and function: The Cardiac Cycle
Trace the path of blood through the heart and throughout the body.
Remember that the major function of the heart is to move blood through the circulation by the application
of pressure. This is accomplished through the work that the heart does during each cardiac cycle. This is
a passive phenomenon.
So remember, the path of the heart is as follows:
Superior
and
Inferior
Vena Cava

Organ
Systems

Right
Atrium

Aorta

Left
Ventricle

Right
Ventricle

Pulmonary
Arteries

Left Atrium

Pulmonary
Veins

Lungs

Compare and contrast diastole and systole.

Remember that a complete sequence of diastole (relaxation)
and systole (contraction) is called a cardiac cycle. The diastole is
the period of relaxation when a chamber if filling with blood, and
systole is the period of contraction when a chamber is ejecting
blood. The heart spends the majority of its time in relaxation or
diastole, and when a situation that goes away two-thirds of the
time, there can be deviations from the normal.
The cardiac cycle can be dissected into a series of major events:
(1) ventricular filling and (2) ventricular emptying. It can be further expanded according to the following
steps: (1) passive filling during ventricular and atrial diastole (where blood is returned to the heart), (2)
atrial contraction (the point where contraction helps filling), (3) isovolumic ventricular contraction (where
the heart has filled but is generating pressure, and no net movement of Oblood),
p e n i n g(4)
a n ventricular
d c l o s i n g o ejection,
f v a lv e s is c o n t r o lle d b y
and (5) isovolumic ventricular relaxation. The whole cardiac cycle occurs about once every second. The
p re s s u re
left and right sides of the heart undergoes the same series of events at
the same time.
W h e n p re s s u re
Structural components, you can allow a pressure gradient.
Valves, what you can start to piece together, you are looking at a system of
tubes.
Valves separate the pressure gradients along these chambers.
Proper blood in a very specic direction, if the valve allows it.

Define pressure gradients across heart valves and

isovolumic states during the cardiac cycle.
With the structural components called valves, you can allow a pressure
gradient. Valves separate the pressure gradients along these chambers.
Thus, opening and closing of valves is controlled by pressure. When
pressure is greater behind the valve, there will be opening and a

is g r e a te r
b e h in d v a lv e

V a lv e o p e n s
P

V a lv e c lo s e s ; d o e s n o t o p e n
in o p p o s ite d ir e c tio n

W h e n p re s s u re
is g r e a te r in
f r o n t o f v a lv e
S h e r w o o d F ig . 9 - 3

10

Isovolumic = constant volume. If there are no open valves in specic stages of the cardiac cycle, there is no change in volume. You can have one situations with changes
When the valves are open, you can change blood volume. You can get movement of blood at these very specic stage
in
To point out, valves are open and the volume can change.
pressure without changes in volume.

Semilunar valves open and empty left ventricle (emptying). AV Valves open, you have an increase in ventricular volu

V e n t r i c u l a r v o l u m e w hV ee nn t rv i ac ul vl ae rs v ao r l eu mc leo sw e h de n v a l v e s a

permission of flow in that direction. However, when pressure is greater in front of the valve, the valve
remains closed and does not allow opening and flow in the opposite
W h e n v a lv e s a r e o p
W h ile a ll t h e v a lv e s o f
direction.
v e n tr ic u la r b lo o d v o l
a c h a m b e r a r e c lo s e d ,
change.
th e re c a n b e n o
Blood flow through valves during the cardiac cycle is dependent on the
S de m i l u n a r v a l v e s o p
c
h
a
n
g
e
i
n
t
h
e
b
l
o
o
pathway. Atrioventricular valves open when the pressure is greater in the
v o l u m e c o n t a i n e d d ien c irt e. a s e i n v e n t r i c u
atria than in the ventricles. As a one-way valve, you need a rigid
v o lu m e ( e m p ty in g )
structure to enforce the one way flow, which explains the role of the
I s o v o l u m i c = c o n s At aV n vt a l v e s o p e n = i n
papillary muscles and chordae tendinae function It is passive, but at the
end of the contraction, the pressure in the ventricles is very low.
v o vl ue mn t er i c u l a r v o l u m e ( f
Semilunar valves open when the pressure is greater in the ventricles than
S h e r w o o d F ig . 9 - 1 7
S h e r w o o d F ig . 9 - 1 7
in the aorta or pulmonary trunk.
When the valves are closed, there cannot be any change in the blood volume contained in it. Thus this is
in an isovolumic state, or a state of constant volume. This allows changes in pressure without changes in
volume. When the valves are open, however, there is a change in blood volume. There is movement of
blood at these very specific stages. When valves are open, ventricular blood volume can change. When
Even though we do study
partssemilunar
of the cell, you needvalves
to understand open,
the whole there is a decrease in ventricular volume (emptying), and when the AV valves
the
heart.
open, there is an increase in ventricular
THere is a cycle, and different components of the cycle.
volume (filling).

20_14

Identify the Wiggers Diagram.

To understand how blood is pumped in an
organized fashion through the heart, it is
essential to know the sequential changes in
pressure and volume that occur in the heart
chambers over time during the cardiac cycle.
This can be observed with a Wiggers diagram.
The Wiggers diagram is a plot of an
electrocardiogram,
chamber
pressures,
chamber volumes, and heart sounds all along
the same time scale.
There is cyclic
generation of high pressure in the ventricle,
and the pressure is used to move blood out of
the ventricle, resulting in cyclic changes in
ventricular volume. Each phase is explained in
the following.
Late diastole is when the left atrial pressure
slightly exceeds the left ventricular pressure.
The left atrioventricular valve is open and
blood passively fills the left ventricle. Left

ventricular volume increases slowly by passive filling.

Atrial systole occurs when the contraction of the atrium causes an increase in atrial pressure and blood is
actively forced into the ventricle to complete filling. Left ventricular volume increases more rapidly during
the active filling phase. This occurs because of the atrial kick, where the blood pressure in the atria
increases and consequently forcing more blood into the ventricles. The atrial kick provides enough force to
where there will be maximal filling, and elevates pressure in proportion to increase in the volume.
In isovolumic ventricular contraction, the left ventricular pressure increases rapidly during systole. Left
ventricular volume remains constant because all of the valves are closed.
Ventricular ejection occurs when the left ventricular pressure exceeds aortic pressure and the aortic valve
opens. The left ventricular volume drops rapidly as contractions continues and blood is ejected into the
aorta. It rapidly declines and stops as soon as the left ventricular pressure is less than the aortic pressure.
Isovolumic ventricular relaxation occurs when the left ventricular pressure drops below the aortic pressure
and the aortic valve closes. The left ventricular volume remains constant because all the valves are
closed. Contraction is going to end at which the pressure external to the valve is going to be greater than
pressure inside the ventricle. The aortic valve is going to shut, and relaxation will occur.
We can further summarize this in the following table:
Phase
Description

Late Diastole
Left AV Valve is
open and

Atrial Systole
Blood is actively
forced into the

Isovolumic
Ventricular
Contraction
No net change in
volume because

11

Ventricular Ejection

Isovolumic Ventricular
Relaxation

Ejection of blood into the

aorta, causing a drop in

Drop in left ventricular

pressure and aortic valve

blood fills the

left ventricle.
Flow occurs by
passive filling.
Pressures

ventricle to
complete filling
by an atrial kick.

valves are closed, but

the left ventricular
pressure increases
rapidly.

left ventricular volume.

closure.

P Aortic > P LA > PPLVAortic > P LA > PPLVAortic > P LV > P LA PLV > P Aortic > P LA P Aortic > P LV > P LA

Calculate stroke volume, ejection fraction, and cardiac output.

From the Wiggers diagram, we can make collect some quantitative information. Two variables of
importance are the (1) end-diastolic volume (EDV) and the (2) end-systolic volume (ESV). End-diastolic
volume (EDV) is the volume of blood in the ventricle at the end of diastole, or the maximal amount that the
ventricle will contain. The end-systolic volume (ESV) is the volume of blood in the ventricle at the end of
systole, or the minimal amount that the ventricle will contain. The difference between these volumes is
referred to as the stroke volume, the amount of blood that is pumped out of each ventricle with each
contraction
(SV =EDV ESV ) . Stroke volume is necessarily a strong determinant of cardiac
function because stroke volume can be increase with an increase in Pheart
r e s s size.
u r e - v Ao lbetter
u m e l determinant
o o p fo r a s
would be the ejection fraction, which is the quotient of the stroke volume and end-diastolic volume

SV
EDV ESV
=
( Ejection Fraction= EDV
)
EDV

Stroke

(3 )

volume is also one of the determinants of cardiac output, which is

the product of heart rate and stroke volume
( CO=HR SV ) .

Is o v o l u m i c
s y s to l i c c u r v e
a c tiv e c u r v e

Relate the Wiggers Diagram to a pressurevolume relationship of the left ventricle.

V entriculaps,mHg

Wiggers diagram can be used to look at the relationship of the ECG

to the cardiac cycle (timing of events).

P -V
lo o p fo r
C a r d ia c ( 2 )
E n d - d i a s to l i c
( 4 ) c y c le
c u rv e
p a s s iv e c u r v e
(1 )

in g le c a r d ia c c y c l

A p r e s s u r e - v o lu m e
lo o p illu s t r a t e s t h e
s e q u e n t ia l d y n a m ic
c h a n g e s in a s in g le
c a r d ia c c y c le .
F o u r d is tin c t p h a s e s

V e n tr i c u l a r v o l u m e , m l

V e n tric u la r p r e s s u r e , m m H g

C o sby
t a n z plotting
o F i g . 4 - 2 0 ventricular
Another way to view changes in pressure and volume during the cardiac cycle is
pressure versus ventricular volume. Ventricular pressure vs. volume must be shown in two plots, known as
active and passive curves. Active curves are pressures developed in a purely isovolumic contraction, with
S u m mduring
a r y ( p h diastole.
ases)
no semilunar valves to open. The passive curve is pressure developed by filling
T h e re a re fo u r
Isovolumic contraction is contraction in which there is no change in
M o h r m a n F ig u r e 4 - 4 A
d is tin c t p h a s e s :
the volume. There is contraction but no change in the volume (going
e je c tio n
Endfrom the passive to the active curve). Isovolumic relaxation is
1 ) F illin g p h a s e
s y s t o lic
relaxation in which there is no change in the volume (going from the
v o l.
A o r tic v a lv e
active to the passive curve). A pressure-volume loop is a plot of
2 ) I s o v o lu m ic
opens
ventricular pressure versus ventricular volume for a single cardiac
c o n tr a c tio n
cycle. A pressure-volume loop illustrates the sequential dynamic
Is o v o l u m i c
S tr o k e
Is o v o l u m i c
r e la x a tio n
3 ) E je c t io n
v o lu m e
c o n tr a c tio n
changes in a single cardiac cycle, and there are four distinct phases
A V v a lv e
in this loop:
fi l l i n g
opens
phase
E n d - d ia s t o lic v o l.
1. Filling Phase: the ventricle is relaxed and is being filled
with blood through the open AV valve.
4 ) I s o v o lu m ic
V e n tr ic u la r v o lu m e , m l
2. Isovolumic contraction: the ventricle contracts while all
r e la x a t io n
the valves are closed. The volume stays constant as the
A b n o rm a l
P e r ic a r d ia l
pressure goes up.
C h a n g e s in c a
r e l a x a ti o n
r e s tr a i n t
3. Ejection phase: the aortic valve opens and blood is
fu n c tio n w ith h
ejected from the ventricle as the ventricle continues to
contract. Volume in the ventricle falls as blood is ejected.
d is e a s e c a n s h
4. Isovolumic relaxation: the aortic valve closes and the
in P - V lo o p
ventricle relaxes. All valves are closed so the volume is
constant while pressure falls.
m e a s u re m e n ts

A p p lic a tio n : P - V L o o p s a r e u s e fu l c lin ic a l

Stroke Volume can be read off of the P-V loop. At the same time,
there are four distinct valve events associated with the PV loop: (1)
AV Valve opening, (2) AV Valve closure, (3) Aortic Valve opening, and
(4) Aortic Valve closure. P-V loops can be used to measure cardiac
work.
Pressure-volume loops have a variety of application. The total area
within the P-V loop is equivalent to the stroke work performed by the
heart

(Work = P dV )

Thus, they can be utilized as

In c r e a s e d c h a m b e r
s ti ff n e s s

C ham ber
d ila tio n

E x a m p le s : d ia s
d y s fu n c tio n ( o n
b o t t o m h a lf o f P
lo o p s a r e s h o w
B r a u n w a ld F ig u r e 1 3 - 1 3

potential clinical tools. Changes in the cardiac function with heart disease can show up in pressure-volume
loop measurements.

12

13

Lecture XXXVI
Cardiac Muscle Structure and Function: Pressure-Volume Relationship
Draw the cardiac cycle in terms of the pressure-volume relationship.
It is important to note that the pressure-volume loop is a plot of ventricular pressure versus ventricular
volume for a single cardiac cycle, and that there are two curves, or boundaries, that the pressure volume
loop must abide by: the (1) isovolumic systolic curve or active curve and the end-diastolic curve or
passive curve. It is also important to remember the four distinct phases and events that occur.
The four phases:
Phase
1

Name
Filling

Pressure
Constant

Volume
Increases

P r e s s u r e - v o lu m e lo o p fo r a s in g le c a r d ia c c y c le

Diagram

Is o v o lu m ic
s y s to li c c u r v e
A V v a lv e
opens
E n d - d ia s t o l i c
c u rv e

entriculaps,mHg

(1 )

Description
Ventricle is relaxed
( 1 ) F i l l i n g p and
h a s e : Tbeing
he
filled with
v e n t r ic le is r e la x e d
blood through the
a n d is b e in g fille d w ith
b l o o d t h r o uopen
g h t h e AV valve. In an
o p e n A V v aideal
lv e .
situation, there
is an atrial kick.

P r e s s uV re en tr- vi c ou lal ur mv o el u ml oe ,ompl f o r a s i n g l e c a r d i a c c y c l e

C o s ta n z o F ig . 4 -2 0

Isovolumic Contraction

Increases

Constant

The ventricle

Is o v o l u m i c
s y s to lic c u r v e

(2 )

A V v a lv e
c lo s e s

V entriculaps,m
Hg

E n d - d ia s to lic
c u rv e
V e n tr i c u l a r v o l u m e , m l
C o s t a n z o F ig . 4 - 2 0

P r e s s u r e - v o lu m e lo o p fo r a

Ejection

Exceeds pressure of the

valve

Sharply decreases
(3 )

A o r tic
v a lv e
opens
I s o v o lu m i c
s y s to li c c u r v e

E n d - d ia s t o li c
c u rv e

( 2 ) I s o v o lu m ic
while all
c o n t r a c t i o n :contracts
The
v e n t r i c l e c o n t r athe
c t s valves are
w h i l e a l l t hclosed.
e v a l v e s a r e The volume
c lo s e d . T h e v o lu m e
as the
s t a y s c o nstays
s t a n t a s tconstant
he
p r e s s u r e g o pressure
es up.
goes up.

The atrial valve

shuts, and there is no
net movement of
s in g le c a r d ia c c y c le
volume.
The aortic valve
( 3 ) E j e c t i o n opens
phase:
and blood is
T h e a o r t ic v a lv e o p e n s
from the
a n d b l o o d i s eejected
je c te d
f r o m t h e v e n t r i ventricle
c le a s
as the
th e v e n t r ic le c o n tin u e s
ventricle continues to
to c o n tr a c t. V o lu m e in
contract.
th e v e n t r ic le f a lls a s

b lo o d is e je c t e d .
V e n tr i c u la r v o lu m e , m l

Isovolumic Relaxation

Decreases

Constant

P r e s s u r eC -o vs t aon zl uo Fmi g . e4 - 2 0l o o p f o r a s i n g l e c a r d i a c c y c l e
A o r tic
v a lv e
c lo s e s
Is o v o l u m i c
s y s to lic c u rv e

entriculaps,mHg

(4 )
E n d - d i a s to l i c
c u rv e

The aortic valve

closes and the
relaxes.

(4 ) Is o v o lu m ic
r e l a x a t i o n : ventricle
T h e a o r t ic
v a lv e c lo s e s a n d t h e
v e n t r ic le r e la x e s . A ll
v a lv e s a r e c lo s e d s o
th e v o lu m e is c o n s ta n t
w h ile p r e s s u r e f a lls .

V e n tr ic u la r v o lu m e , m l

S u m m a r y ( v a lv e e v e n t s )
V e n t r i c u la r p r e s s u r e , m m H g

M o h r m a n F ig u r e 4 - 4 A

A o r tic
v a lv e
c lo s e s

e je c tio n

C o s t a n z o F ig . 4 - 2 0

Stroke volume can be read from the PV loop, which is the difference
between the end-diastolic and end-systolic volumes.

A o r tic
v a lv e
opens

T h e re a re 4
d is t in c t v a lv e
Is o v o l u m i c
e v e n ts .
Identify
key points on the pressure-volume loop.
Is o v o lu m ic
r e la x a ti o n
c o n t r a c t io n
There
are
four
key points on the pressure volume loop:
A V v a lv e
opens
A V v a lv e
1. AV Valve opens (end of isovolumic relaxation)
c lo s e s
2. AV Valve closes (beginning of isovolumic contraction)
V e n tr ic u la r v o lu m e , m l
3. Aortic Valve Opens (end of isovolumic contract/beginning of
ejection)
4. Aortic Valve Closes (start of isovolumic relaxation)

Compare and contrast isovolumic relaxation and contraction.

Isovolumic contraction and relaxation are two terms that assign changes in pressure while under constant
volume, because all the valves are closed. Isovolumic contraction is exhibited by an increase in pressure
under constant volume and occurs prior to ejection, while isovolumic relaxation is exhibited as a decrease
in pressure under constant volume, occurring after ejection.

List the parameters that determine cardiac output.

Cardiac output is the volume of blood pumped by each ventricle per minute. In order to get at
determinants of cardiac performance, we can break down cardiac output into its determinants. Cardiac

14

output is the product of heart rate (HR) and stroke volume (SV) or
CO=HR SV
can be altered by changing either heart rate or stroke volume (or even both).

. Cardiac output

Calculate cardiac output and describe and how it can be altered.

Remember that cardiac output is the product of heart rate and stroke volume (CO=HR SV ) . For
example, if a patient has a heart rate of 70 and a stroke volume of 70 mL/beat, we can then calculate
cardiac output by the following:

CO=HR SV =70

beats
mL
mL
L
70
=4,900
5
min
beat
min
min

Relate changes in contractility, preload, and afterload to the ventricular

pressure-volume relationship.

F o r a g iv e n e n d d ia s t o lic
v o lu m e t h e v e n t r ic u la r
p r e s s u r e d e v e lo p e d
d u r in g is o v o lu m ic
c o n t r a c 9 o n is g r e a t e r.

E f fe c t o f a s u d d e n a I e r lo a d o n P V c u r v e s
V e n tr ic u la r e n d -d ia s to lic v o lu m e

V e n tr ic u la r p r e s s u r e

Cardiac contractility is the strength of contraction of the cardiac muscle at a

given end-diastolic volume, or a given amount of filling volume. Heart can
change its ability to contract when there is a change in preload. When
contractility is increased for a given end-diastolic volume, the ventricular
pressure developed during isovolumic contraction is greater. There is a shift
in the pressure-volume relationship to the left in increased contractility, and
to the right in decreased contractility.

V entriculaps

In c r e a s e d c
o n t r a c 9 lit y
Heart rate is one of the 4 determinants of cardiac performance, but is dictated by external
stimuli,
particular sympathetic or parasympathetic stimulation. The other three fall
In c r e a s e d c o n t r a c t i l i t y
under the variable of stroke volume. Stroke volume can be altered in three
E x a m p le
C o n tr o l
different ways: (1) changing contractility, (2) changing the preload, and (3)
W h e n c o n t r a c 9 lit y is
changing the afterload.
in c r e a s e d :

Shift in the left of the end-systolic PV relationship!

Released the constraint from the intrinsic properties based upon the
level of contractility. You can maintain stroke volume to maintain
contractility.

W h o le h e a r t :
a I e r lo a d ,le a d s t o
The other two determinants of cardiac performance (preload and afterload)
s t r o k e v o lu m e u p o n
Is o v o l u m ic
have to do with the workload placed on the heart either before or after
c o n tr a c tio n
co n tra c9 o n
contraction begins. Preload is the workload imposed on the heart before
contraction begins (end-diastolic volume). Afterload is the workload imposed
on the heart after contraction begins (having to do with the end-systolic
V e n tric u la r v o lu m e
volume). Remember that end-diastolic volume has to do with the volume of
blood in the ventricle at the end of diastole, or the maximum amount that the ventricle will contain. EndDiastolic volume determines how stretched out the cardiac muscle fibers are. On pressure-volume curves
(on the whole heart), an increase in preload leads to an increase in stroke volume upon contraction, based
on the Frank-Starling Relationship. Whatever comes into the heart must affect the relationship. If you
increase filling, you increase the end-diastolic volume. It needs to undergo a contraction that
In c r e imposes
a s e d c o n t r aac 9 lit y
load against it.
Increased afterload!
Heart will continue to generate
pressure until ejection can occur!

Handle that increase

in afterload by elevating pressure!
Reach a different end-systolic pressure volume relationship!

Continue to eject until you reach the end of the end-systolic!

Do something with that extra volume of blood! Heart will shift that pressure volume loop. If there is no external stimulus, it will shift to t
to maintain stroke volume. Stroke volume is different before increase. It will shift to increase stroke volume to match the stroke volume t
there
before.
This is done by intrinsic mechanisms! There heart can reset itself without any external input.

In c r e a s e d c o n tr a c tility

V entriculaps

For the whole heart, afterload is related to the arterial blood pressure because
C o n tr o l
that is the pressure that the heart must work against. Remember that in
order for ejection of blood to occur, the left ventricular pressure must be
greater than the aortic pressure, and the left ventricular pressure must
increase until ejection occurs. An increase in afterloads leads to a decrease in
stroke volume upon contraction. The heart will continue to generate pressure
until ejection can occur. The heart will handle this increase in afterload by
elevating pressure and eventually reach a different end-systolic pressure
V e n tric u la r e n d -d ia s to lic v o lu m e
volume relationship. Eventually, the heart will shift to a different pressure
volume loop. If there is no external stimulus, it will shift to the right to maintain stroke volume. Stroke
volume is different before increase. It will shift to increase stroke volume to match the stroke volume that
was there before. This can be done by intrinsic mechanisms. The heart can reset itself without any
external input.

E x a m p le
W h e n c o n t r a c 9 lit y is
in c r e a s e d :
F o r a g iv e n e n d d ia s t o lic
v o lu m e t h e v e n t r ic u la r
p r e s s u r e d e v e lo p e d
d u r in g is o v o lu m ic
c o n t r a c 9 o n is g r e a t e r.

Shift in the left of the end-systolic PV relationship!

Released the constraint from the intrinsic properties based upon the
level of contractility. You can maintain stroke volume to maintain
contractility.

How does this all fit together? Remember that P-V loops can be used to measure cardiac work. The total
area within the P-V loop equals the stroke work performed by the heart. The dynamic properties of the
whole heart are based on the fundamental dynamics of an individual sarcomere.

15

Lecture XXXVII
Cardiac Muscle Structure and Function: Components of Cardiac Muscle
Differentiate between skeletal muscle cells from cardiac cells.
Cardiac cells and skeletal muscle cells rather distinct in terms of function and histology, giving distinct
orientations to the fibers. The skeletal muscle cell is long, multinucleated and striated. The cardiac
muscle has one nucleus, striated, and branched. It contains intercalated discs and gap junctions. This is
important later for the cardiac muscle for cell-cell communication and the all-or-none activity observed in
the cardiac muscle.
Distinct
the bers.
Skeletal muscle cells are distinctly different
fromorientation
cardiac to
cells
by the following:
Distinct
orientation
Characteristic
Skeletal
Muscle to the bers.
Cardiac Muscle
Diagram

P o l la r d a n d E a r n s h a w F ig u r e 3 9 - 2
P o lla r d a n d E a r n s h a w F ig u r e 3 9 - 2

Morphology
Fiber Diameter (m)
Fiber Length (m)
Junctions between fibers
Contraction Speed

Long, multinucleated, striated

10-100
100-3000,000,000
None
Fast

D o w n l o a d e d f r o m : S tu d e n tC o n s u lt ( o n 2 6 M a r c h 2 0 1 0 0 7 : 1 1 P M )
2 0 0 5 E ls e v i e r

D o w n lo a d e d f r o m : S t u d e n t C o n s u lt ( o n 2 6 M a r c h 2 0 1 0 0 7 : 1 1 P M )
2 0 0 5 E ls e v ie r

Branched, central nucleus, striated

10-20
50-100
Intercalated Discs
Moderate

Diagram a sarcomere during diastole and systole.

What is necessary to understand is that the dynamic properties of the whole heart are based on the
fundamental dynamics of an individual sarcomere. This is important
because each sarcomere is going to contribute to the ultrastructure
of the heart. If one was to take a cross-section of a sarcomere, they
can note that there are proteins interdigitating with one another in a
specific orientation in an ordered, regular pattern. The sarcomere
has four landmarks of interest:
I band, also known as the Isotropic band
A band, also known as the Anisotropic band
H zone, which is bright
M line, or Middle Line. The M line is found in the H zone.
In a state of diastole, or a relaxed state, the sarcomere as a whole
would lengthen. In a state of systole (or contraction), the sarcomere as a whole would decrease in length.
These mechanisms are to allow maximal or minimal interactions of two specific fibers, known as actin and
myosin.

Distinguish between the thin filaments from the thick filaments.

There are two types of fibers that are found in the sarcomere, known as thin filaments and thick filaments.
Thin filaments are polymers that consist of actin monomers, while thick filaments consist of myosin. Both
these two contribute to the sliding filament theory of contraction. By experimentation, scientists found
that if the relative force between actin and myosin is generated at each of a series of points in the region
of overlap in each sarcomere, then the tension should be proportional to the number of these points, and
therefore to the width of the overlap. They also found that a possible driving force for contraction in this

16

E x p e r i m e n ta l a r r a n g e m e n t o f th e B io C A T u n d u l a to r b e a m l i n e f o r X - r a y d iff r a c tio n

Look very closely at the structure of muscle with various techniques (X-ray diffraction)
m u s c le
m ir r o r
X -ra y s
model might be the formation of actin-myosin linkages when
b a th
Take a muscle, and activate it, and compare the diffraction band. The
adenosine
pattern then
changes. Based upontriphosphate
pattern of changing diffraction(ATP),
pattern, you canhaving
begin to derive previously displaced actin
information at the molecular level.
e v a c u a t e d f lig h t tu b e
from myosin, is enzymatically split by the myosin head. In short,
u n d u la t o r X - r a y s o u r c e
( X - r a y r e f le c t io n s )
le c t r o n s )
these proteins, whenAccelerate another( eelectron,
the movement of electron releases
overlapping, dictate theX-rays.
a c tin
m y o s in
1 ,1
contraction.
It should
also be noted that the
1 ,0
speed of contraction of Take the electron and would undulate it fast (generating high-intensity X-rays)
and blast into muscle, it will reect based on the orientation of the molecules.
X -ra y s
a muscle is directly From that information, we can perform calculations based on an image.
proportional
to
the
speed of contraction of the sarcomere.

C CD
d e te c to r

One can observe the structure and function by x-ray

crystallography, a technique used to closely examine the
structure of muscle. This involves the energy of electrons. When
electrons accelerate, the movement of the electrons (in the presence of deflecting agents such as
magnets), can allow the release of X-rays from the electron. One can take the electron and undulate it
extremely fast, generating high-intensity X-rays and direct it towards a muscle. The diffraction will reflect
based on the orientation of the molecules. From the information, calculations can be done based on the
image produced. If a muscle is forced into action by activation and then analyzed by X-ray diffraction,
there are noticeable changes in the diffraction pattern. Based on these changes of the diffraction pattern,
scientists can gather information at the molecular level. They can look specifically at the pattern of
extrusions, discerning what is happening at the different heads, and can produce a structure of a muscle.
Closer examination will show that the extrusions play a role in contraction.

Draw a schematic of the functional domains of myosin.

This is the just the myosin head. Able to identify within this myosin head, there is an ATP
binding pocket, actin binding domain, regions of association (RLC and ELC).
Turn this region to the myosin S1 region. The S2 region is the hinge domain. The hinge
is critical to allow exure of the myosin head, which is important in the overall structure
ATP
M y o s in S 1
and function of the muscle.
b in d in g p o c k e t
ELC
a c tin
b in d in g d o m a in

RLC

LMM is the main component of the

thick lament.
S2
S1

LM M

S1 is a fraction of overall amino acids, but is major constituent in terms of amino

866
1 acid
1938
amounts.
S1
S2
LM M
CO O H
N H 2 very specically
Bind
in a specic fashion.
These individual
monomers

The myosin head consists of three function sites: (1) ATP binding
pocket, (2) actin binding domain, (3) regions of association (RLC and
ELC). The myosin head consists of the S1 region. The hinge domain
is considered the S2 region. The hinge domain is critical to allow
flexure of the myosinhead, which plays a role in the structure and
function of the muscle. The myosin head, though the smallest, is
considered the majority in terms of amino acid amounts.
Myosin exists as a compilation of molecules in the thick filament.

can
associate with another myosin to make a coiled coil. It is
haveMyosin
to be assembled
to
this ordered actin. This process that is tightly regulated. THere are a numbera
of things
to occur
heterohexamer,
consisting of 2 myosin and 4 light chains. There
m y o s i n r o d It is able to get into that sarcomere and
g l o actin
b u l a r h and
e a d myosin together
n e c k / h i n g ein the sarcomere.
in a heart to get
are different types of myosin (alpha and beta myosins arising from
align itself in that lament.
marrow
A cLight
> n A
s s emyosin
m b ly

different genes), and like myosins do not have to

with one another. In cardiac tissue, humans
have both alpha and beta. In humans, the majority of
myosin is beta-myosin. Alpha myosin is more prominent
in smaller animals, and beta is more prominent in large
animals.
In disease states, there is a higher
concentration of beta myosins. Intuitively, there is a shift
Requirement to have more than one monomer
N u c le a ) o n together to make the lament (three or more)
that is measurable and indicative of disease. Coiled-coil
G ro w th
dictates packaging of the filament. Though it does exist
E lo n g a ) o n Put it to its very specic length.
as a heterohexamer, the x-ray diffraction cannot
distinguish between one head or another. The cause has
Actin can actually bind to ATP, and when ATP is bound to actin
not been addressed fully. However, it should be noted
A T P d e p e n d e n t p r o c e s s it readily associates with other monomers.
ATP hydrolysis destabilizes the system ATP allows association with other monomers.
that myosins have a very specific orientation and polarity.
on one end compared to the other,
What
can
be
examined
is
how
those
thick
filaments
associated with these thin filaments, consisting of
There
are
proteins
associated
with
thick
and
thin
laments.
regulated by certain proteins that
regulateactin.
length of growth and lament
It has a very specic length. The length is relatively constant.
associate
The idea is to go from actin to the long chain. This is a highly regulated
event.

length.

Binding occurs very specifically between actin and myosin. There are proteins associated with the thick
and thin filaments. Actin monomers have to be assumed to create the thin filament. This process is
tightly regulated. There are a number of events to occur in the heart to force actin and myosin together in
the sarcomere. It is able to get into that sarcomere and align itself in that filament. It has a specific,
constant length, with the main goal is to form a long chain from actin monomers. This is also tightly
regulated. There are three steps involved in actin assembly:
1. Nucleation: Requirement to have more than one monomer together to make the filament (at least
three or more).
2. Growth
3. Elongation: Using the monomers to create the polymer of a specific length.
All in all, this is an ATP-dependent process. The only difference between the actin and myosin structure is
really in the difference in size.
These proteins are turning over regulary. Once the length has been

17

established, there are processes that will put monomers on different ends. Actin can actually bind to ATP,
and when ATP isbound to actin it readily associates with other monomers. ATP allows association with
other monomers. However, ATP hydrolysis destabilizes the system on one end compared to the other,
regulated by certain proteins that regulate length of growth and filament length.

18

Lecture XXXVIII
Cardiac Muscle Structure and Function: Components of the Sarcomere
List and describe the 4 levels of protein organization.
Remember that there are four levels of protein organization:
1. Primary the amino acid sequence that is yielded from translation at the ribosomes.
2. Secondary conformational changes of the backbone either into an alpha helix or to a beta sheet.
3. Tertiary three-dimensional arrangement (or motifs) of secondary structural elements. This is
taking into account the protein is sitting in real space, and needs to fold into a specific interaction.
If may require regulatory proteins in order to accomplish the tertiary structure.
4. Quaternary Formation of multiple subunits from the motifs. Proteins and subunits associate with
one another, combining
into dimers. Channels are typically multiple subunits of different genes.
Myosin assembled into thick lament. There are TWO myosin heads, but this myosin head is where the business end of the myosin molecule is.
There are mutations in that thick lament that does not very much profound disease.

We do have proteins arranged

in a very specific order.
Myosin acts as an ATPase.
specific arrangement.

It does not happen spontaneously and has a

M y o s in e x is t s a s a
theOnestructural
organization
of the
thick
and
filament
e t eisr aothin
h e x a mthat
e isr huge. It isin
LookCompare
at the myolament.
of the main structures
that is of focus of current
research
is titin. hTitin
protein
gian a
protein that
extends
from one sarcomere Differentiate
to the middle of the sarcomere.
sarcomere.
between actin filament structure and myosin
structure.

is a heterohexamer and coiled-coil. Imparts ideas of multiple levels of structure.

VariousFilament
components of titin,Myosin
which
allows
it lament.
to
be quite exible. It is the main protein that provides structural
Ordered
packaging
in the thick
Thick
Thin support and plays a role in the passive
properties.
The ability to generate
force
isin an
active
property. Systolic function is an active property. Well,
during relaxation, they are in a passive state.
Start piecing this
together
howMyosin
proteins
interact.
Component
Actin
Diagram
Functioning
on the
passive end
plays a role in disease
H e t e r o h e x a m e r
states.

1 . C o ile d c o il
Women with diastolic function perturbed.
Not always the case, but seen more in women
than
men.
X r a y c r y s t a llo g r a

2 . 2 m y o s in s ,4 lig h t
c h a in s

p h y

3 . O r d e r e d p a c k a g in g in a
t h ic k fi l me n t

We know that it exists as a heterohexamer. It can exist whether two of the

same or two of the different.

P o lla r d a n d E a r n s h a w F ig .3 9 7

p a s s iv e p r o p e r 8 e s

It can form these different associations to have the same types of myosins.

Main Form of
Arrangement
Arrangement

T i8 n

Coiled-Coil

Double Helix Monomers

It is important to remember that myosin exists as

a heterohexamer, confirmed by x-ray
crystallography. It is in coiled coil, and in ordered
packaging in the thick filament.

Requires an ATP-dependent process that involves individual actin

units to accumulate in a specific manner. They can interact with
other molecules and regulatory units to ensure assembly,
disassembly, regulation of length, and stability.

Diagram titin and troponin structure within a sarcomere.

Protein
Placement in
Sarcomere

Titin

Myomesin

Troponin

Location

Found in I-band. M-line, and Zline of sarcomere.

Molecular spring responsible for
the passive elasticity of muscle.

Found in the M-band of muscle sarcomeres in

association with M-protein.
Found in both slow and fast fibers. Molecular spring
that protects the sarcomere and stabilizes during
intense or sustained stretching.
Involved in anchoring thick filaments to other
filaments, specifically titin.

Found in the sarcomere.

Function
Characteristics

Largest known protein.

19

Attached to the protein

tropomyosin and lies on actin
units.
Various types depending on
function.

It should be noted that there is profound interest in the troponins, which impart regulation on the actin
filament. The crossbridge interaction can be acting in a controlled manner. Troponin C is a calcium-binding
protein. Troponin I links troponin C to entire complex (as an inhibitory protein). Troponin T binds to
tropomyosin, which links the whole complex together. Overall this complex acts as a functiona unit, and
each part cannot be separated and analyzed in a vacuum.
In the Z-disk, there are a whole lot of proteins. What is known is that there are various defined signaling
pathways, as there are for other cells. Thought of having these proteins lead to signaling of one another.
It is a highly regulated system in which there are proteins to do their job. It is clearly a complicated
structure, and goes beyond just a structural entity where it holds the filaments together. There are
intracellular signals going back and forth as well. There are a lot of proteins associated with the Z-disk.
This constants yields a recurring them that the primarily structural proteins have an important role in the
signaling of the molecule. Based on the structures in the proteins, scientists were able to piece together
the concept of the sliding filament theory.
Dystrophin is another example of a protein involved in structure and signaling, and plays a role in the
muscle cells association with the matrix. It occurs through very specific proteins. It dos have the ability
to link the extracellular matrix. Not only this can provide structural support but plays a role in signaling.

20

Lecture XXXIX
Cardiac Muscle Structure and Function: Mechanism of Muscle Contraction I

S lid in g F ila m e n t t h e o

State the sliding filament theory of muscle contraction.

The sliding filament theory of muscle contraction describes the
mechanism by which muscles contract.
Basically, scientific
observations showed that in periods of extension and contraction,
there were signs of cross-bridging occurring within the sarcomere.
Myosin acts as the molecular motor (such as a ratchet) and actin
acts as the thin filaments that transmit the force generated by
myosin to the ends of the muscle. The mechanism is in the
following:
1. Myosin heads binding to passive actin filaments at the
myosin binding sites.
2. Upon strong binding, myosin and actin undergo
isomerization (myosin rotation) extending an extensible
region in the neck of the myosin head.
3. Shortening occurs when the extensible region pulls the
filaments across each other, while myosin remains attached
to the actin.
4. The binding of ATP allows myosin to detach from actin. ATP hydrolysis then occurs to allow the
myosin head to reset, allowing binding of actin.
5. The collective bending of numerous myosin heads in the same direction to combine and move the
actin filament relative to the myosin filament, resulting in muscle contraction.
Length is equivalent to volume. You have these myocytes that surround the volume. Even though
we think volume is equivalent to length, it is slightly untrue. Generating force on those wall in a volume. They're not exactly equivalent. If you take an
elastic structure, there is a limit to that elasticity. But, as you increase the volume of that elastic structure, the pressure goes up. There is a limit to that.
As you approach the end of the elastic properties of that structure, pressure has to go down.
Stress on the wall maintains linearity.
When we think about pressure and tension,
If you think about the steepness of the cardiac
they are not exactly equivalent.
relationship,

Draw the length-tension relationship for skeletal muscle and cardiac

muscle.
there is a larger change in tension.

Reach point where there are no more myosin heads.

The amount of heads are decreasing as you increase
length. Stretching the actin laments beyond the thick

lament.
The length-tension relationship is the relationship relates
length of the fiber and the force the fiber produces at the
Even though they are the same, they have different proteins.
They have the same basic relationship, but cardiac has a steeper.
length. It essentially has two curves: an (1) ascending
Slightly shifted to
the right and is
curve (that exhibits an increase in tension with an increase
steeper.
Overlap is suboptimal. for every increase in volume, there will
be a decrease in force.
If you tkae a muscle, and hook it up to a force transducer and length control
in length) and a (2) descending curve (with a decreased
Active tension. They're very
specic properties that make it
tension with an increasing length). The length refers to
different from skeletal to
cardiac muscle.
length of the isolated fiber and dependent upon position of
actin and myosin filaments.
When a muscle fiber is
Direct linear decline. As you
increase from 2.5 to 3, there is a decrease
stretched to the minimal overlap and stimulated Leads
byto important
ancharacteristics. We're discussing sarcomere length. They have a specic range of
in tension.
length. If they measure all the laments, they are not individually the same length, but as a whole
can
electrode, the measured contraction force is minimal. There
is
be the same length.
a reach point where there are optimal myosin heads, and One
atthingthat
to appreciate is to be able to recreate the graph.
Velocity increases with decreasing
force!
point the amount of heads are decreasing as the length is
There is a direct relationship between
increased, essentially stretching the actin filaments beyond the
tension and length.
As you are generating tension with optimal length.
Ascending limb: Increase tension with increasing length.
thick filament.. The amount of heads interacting with the
More actin
myosin interact. There is a point where maximal myosin
Descending Limb: Decreased tension with increasing
interact.
length.
filament is decreasing as you increase the length, stretching the
actin filaments beyond the thick filament.
This leads to
important characteristics of the sarcomere. They have a specific
range of length. If they measure all the filaments, they are not
individually the same length, but as a whole can be the same
length.
S h ie ls , H . A . e t a l. J E x p B io l 2 0 0 8 ;2 1 1 :2 0 0 5 -2 0 1 3

F ig u r e 3 9 - 1 2
The reasoning of the curve is that length is equivalent to
volume. There are myocytes surrounding the volume. With the
volume, there is a generated force on the wall. If you take an elastic structure, there is a limit to that
elasticity. But, as you increase the volume of that elastic structure, the pressure goes up. There is a limit
to that. As one approaches the end of the elastic properties of that structure, pressure has to go down.
What can also be noted is that velocity also increases with the decreasing force, mainly because there is a
greater change in the number of actin-myosin interactions. The difference between the curvilinear
relationships for skeletal and cardiac muscle is mainly due to the different proteins that are found in the
cardiac muscle.
D o w n l o a d e d fr o m : S t u d e n t C o n s u lt ( o n 2 9 M a r c h 2 0 1 0 1 0 : 2 9 P M )
2 0 0 5 E ls e v ie r

Even though they are both muscles, they have different proteins. They may exhibit the same basic
relationship, but cardiac tissue has a steeper curve that has a greater shift to the right, giving cardiac
muscle a greater change in tension as a function of sarcomere length. What is important is that force is
proportional to the number of strongly bound cross-bridges.

21

Compare the length-tension relationship for cardiac muscle and the

pressure-volume relationship of the heart.
The length tension relationship can be related to the heart because there is a dramatic increase in tension
development with small changes in length. There is a huge reserve in order to attain
larger volumes. There is a lot being learned about the pressure-tension relationship O 2 u s e d
that can actually determine and dictate disease states. Diastolic dysfunction can lead m l / h r
to heart disease. This is the passive length-tension relationship. One can infer that
with changes in length that there are going to be changes in tension. Remember in
the pressure-volume relationship, that P-V loops can be used to measure cardiac work.
E x te r n a l w o r k
The total area within the P-V loop equals the stroke work performed by the heart.
K a tz F ig . 1 6 .9

M y o c a r d ia l O 2
c o n s u m p t io n g o e s u p
w it h in c r e a s in g w o r k
p e rfo rm e d .
We can measure blood going into the heart and blood coming out.
Now that oxygen is being used with the Krebs cycle.
As you increase the external work, myocardial oxygen consumption goes
up.
You can start to look at how the heart's working appropriately.

Experimentally, studying the movements of an intact twitching

muscle of a frog can do this. A microscope apparatus will often
utilize a force transducer and a motor arm that adjusts the
length finely, and with light diffraction, measure the changes in
length and observe the force generated. This can be done
because muscle is striated, so shining a light yields a diffraction
Myosin is a molecular motor to do work. In the context of the heart, it is in the form of
pattern.
Remember that light diffraction can allow
contraction.
measurement of the specimen under study
by allowing
refraction
of light to a larger medium.
Basically,
there is a load
of the heart.

This implies that there is something being used to generate work.

Cardiac contraction requires energy. Myosin

The myocardial
O 2theconsumption
goes up with increasing work
uses ATP to move
load somewhere else.
performed. One can measure blood going into the heart and blood
coming out. As the external work is increased, myocardial oxygen
consumption goes up. This implies that something is being used to
generate work.

Differentiate between a crossbridge and myosin.

Cross bridges is simply are globular heads of a myosin molecule that
project from a myosin filament in muscle and in the sliding filament
hypothesis of muscle contraction area held to attach temporarily to an
adjacent actin filament and draw it to the A band of a sarcomere between
the myosin filaments. Myosin is the molecular motor to do work. In the
context of the heart, it is in the form of contraction. Motors bind stably to
a support or cargo and transiently to a cytoskeletal fiber (actin filament
or microtubule). Energy liberated by ATP hydrolysis prouces force to
stretch an elastic element somewhere in the physical connection
between the cargo and the cytoskeletal fiber. The resulting motion
depends on whether the force in the spring exceeds the resistance of the
fiber or the cargo.
Scientists have been able to use various techniques to observe as
extended and contracted conditions, which exhibit extensions from the
thick filament onto the thin filament. What they were able to identify was
F ig u r e 3 6 - 2 G e n e r a l f e a tu r e s o f A T P a s e m o to r s . M o t o r s b in d s t a b ly t o a s u p p o r t o r c a r g o a n d t r a n s ie n t l
cross-bridge formation.
A lot of these interactions was based on biochemical studies. Based upon experimentation, there is actin myosin
interaction.
The T is ATP. Those are various states to go from hydrolysis of ATP to the movement of the myosin.
WE have to include these into the biochemical state because there are states with no actin bound.

c y t o s k e le t a l f ib e r ( a c t in f ila m e n t o r m ic r o tu b u le ) . E n e r g y lib e r a te d b y A T P h y d r o ly s is p r o d u c e s f o r c e to s t r
e la s tic e le m e n t s o m e w h e r e in th e p h y s ic a l c o n n e c tio n b e t w e e n th e c a r g o a n d t h e c y to s k e le ta l f ib e r . T h e
m o t io n d e p e n d s o n w h e t h e r t h e f o r c e in t h e s p r in g e x c e e d s t h e r e s is t a n c e o f th e f ib e r o r th e c a r g o

Diagram the
crossbridge.

ATPase

cycle

of

the

myosin

What should be known is that myosin can be utilized as an ATPase.

Myosin in the presence of actin rapidly hydrolyses ATP. If a scientist
placed myosin alone with ATP, hydrolysis will occur. Addition of actin
will allow hydrolysis to occur at a greater rate. Removal of actin will
yield a slower reaction rate.
What also should be remembered is that myosin has 3 parts:

22

a b s e n c e o f a c t in

F i g u r e 3 6 - 5 M y o s i n A T P a s e m e c h a n i s m s . A , A d i a g r a m o f t h e a c t o m y o s in A T P a s e c y c le o f s t r ia t e d m u s c l e m y o s in - I I s h o w i n g t h e a c t i n fi l a m e n t (A ) , m y o s i n h e a d ( M ) ,
A T P (T ) , A D P (D ), a n d i n o r g a n ic p h o s p h a t e ( P ) . T r a n s i e n t - s t a t e k i n e t i c s r e v e a l e d t h e m a j o r c h e m i c a l in t e r m e d i a t e s a n d t h e r a t e c o n s t a n t s f o r t h e i r t r a n s it i o n s . A r r o w s a r e
p r o p o r t i o n a l t o t h e r a t e s o f t h e r e a c t io n s , w i t h s e c o n d - o r d e r r e a c t i o n s a d j u s t e d f o r p h y s i o l o g i c a l c o n c e n t r a t i o n s o f r e a c t a n t s . O n e o r tw o a s t e r i s k s i n d i c a t e c o n f o r m a t i o n a l
c h a n g e s i n t h e m y o s i n h e a d in d u c e d b y A T P b i n d i n g a n d h y d r o l y s i s . M y o s i n w i t h o u t n u c l e o t i d e ( M ) a n d m y o s i n w i th A D P ( M D ) b i n d m u c h m o r e t i g h t l y to a c t i n f i l a m e n t s
t h a n d o A M T a n d A M D P . T h e w e a k l y b o u n d A M T a n d A M D P i n te r m e d i a t e s a r e i n a r a p i d e q u i li b r i u m w i t h f r e e M T a n d M D P . T h e b e i g e h i g h l i g h t s h o w s t h e m a in p a t h w a y
t h r o u g h t h e r e a c t i o n . B , T h e p o s t u l a t e d f o r c e - p r o d u c i n g s t r u c t u r a l c h a n g e s i n t h e o r i e n ta t i o n o f t h e l i g h t - c h a i n d o m a i n ( p u r p l e a n d b l u e ) c o u p le d t o t h e m y o s i n A T P a s e
c y c l e . ( B , B a s e d o n s k e t c h e s a n d d a t a f r o m R . V a l e , U n i v e r s i ty o f C a li f o r n i a , S a n F r a n c i s c o , a n d R . M i l l i g a n , S c r i p p s R e s e a r c h I n s t it u t e , L a J o ll a , C a l i f o r n i a . )
D o w n lo a d e d f r o m : S tu d e n t C o n s u lt ( o n 3 0 M a r c h 2 0 1 0 0 1 : 2 1 A M )
2 0 0 5 E ls e v ie r

D o w n l o a d e d f r o m : S tu d e n tC o n s u l t ( o n 3 0 M

1.
2.

3.

Myosin S1: Takes up most of the amino acids in the whole

sequence of the molecule
Neck/Hinge Region (S2): Exhibits flexibility, which plays a
role in the myosins ability to interact with actin. Decreases
in flexibility can affect interaction between myosin and
actin.
LMM

In the presence of ATP, there is a presence of actin and myosin, and

allows a conformation change in the myosin molecule. With addition
of troponins and tropomyosin, there is now regulation of the system.
If myosin can activate ATP faster, there is possible hindrance to the
actin and myosin relationship. When going from a relaxed to a
contracted state, there is a shift in the molecular mass to a different
area. Once the muscle is activated, limited scattering occurs and forces a concentration shift into the
central region. It essentially allows conglomeration to a single mass. Actin and myosin interact in a very
specific way, arranging itself in a barbed end and a pointed end. Myosin binds to actin with a given
polarity. There is a specific interaction in order for a contracted and relaxed state to occur, and specific
orientation of the head required relative to the molecule. There must be a change in the myosin
conformation to allow it to shift towards the middle of the sarcomere. There are two states of the myosin
head, known as the ADP-Pi and the ADP/nucleotide-free. This shows that there must be a release of the
inorganic phosphate in order to have the conformational change. This reaction shift eventually combines
to form what is known as the cross-bridge cycle. This basically establishes
the mechanism that actin and myosin interact and permit muscle contraction.
The cross-bridge cycle is acts by the following steps:
1. Resting fiber; cross bridge is not attached to actin
2. Cross bridge binds to actin
3. Inorganic phosphate is released, causing conformational change in
myosin.
4. Power stroke causes filaments to slide, and ADP is released.
5. A new ATP binds to the myosin head, allowing it to release from
actin.
6. ATP is hydrolyzed, causing cross bridge to return to its original
orientation.

Identify the powerstroke of the crossbridge cycle.

The powerstroke of muscle contraction occurs when actin rebinds to myosin,
spurring the release of the terminal phosphate group of ATP, which allows the
myosin molecule to reverse the conformational change while bound to actin.
This is important because the conformation change is required in order for the
interaction and consequential contraction.
Based on the illustration, the myosin heads are in the ADP-P i state and
catalytic cores bind weakly to actin. One the myosin head docks to an actin
subunit, the inorganic phosphate is released. Phosphate release results in an
increase in the affinity of the myosin head for actin and allows the myosin to
the post-stroke, ADP state. The exact distance may vary from cycle to cycle
depending upon the initial prestrike vinding configuration of the myosin on
actin. After the execution of the stroke, ADP dissociates and ATP binds to the
empty active site, causing the catalytic core to detach from actin. The lever
arm then re-cocks the myosin head back to its pre-stroke state.

23

M u s c le m y o s in : d im
f ila m e n t ( t o p ) b y a c
h e lic a l a c t in f ila m e n
b lu e a n d its m e c h a n
s u r r o u n d in g lig h t c h
m o v ie , t h e m y o s in h
c a t a ly t ic c o r e s b in d
a c t in s u b u n it ( g r e e n
P h o s p h a te r e le a s e
s w in g s t h e c o n v e r t e
y e llo w t o r e d ) . T h e
e x a c t d is t a n c e m a y
p r e s t r o k e b in d in g c o
s tr o k e , A D P d is s o c i
c a u s e s th e c a ta ly tic
b a c k t o it s p r e s t r o k e

Lecture XL
Cardiac Muscle Structure and Function: Mechanism of Muscle Contraction
II
List major thin filament regulatory components (proteins).
The major thin filament regulatory components are (1) troponin
C, (2) troponin I, and (3) troponin T. They ultimately will play a
role in the formation of a regulatory complex and move the
tropomyosin to allow exposure of the myosin binding sites on
actin.

Define the steric hindrance model of muscle

contraction.

think about the

cross-bridge cycle that is
different
from the cardiac cycle.
As you get this rearrangement of proteins, things are lifting off and as you open the site, myosin can bind and start ATPase cycle and start
over.

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Another model that is under discussion is the steric-hindrance model,
which is an extension of the sliding
filament model of muscle contraction. It simply states that the
interaction of actin and myosin can be physically blocked, and
requires a conformational change in order to allow the attachment of
myosin to actin. There is a blockage of atin and myosin that the
troponins and tropomyosins are responsible for. This blockage is
essentially what is responsible for the selectivity. ATP hydrolysis is
required to initiate the myosin head pivoting and allow interaction.
Steric hindrance of the contractile cycle can occur by tropomyosin
and troponin.
Tropomyosin filaments periodically studded with
troponin run along the actin double helix, blocking the myosinbinding site. With an influx of calcium, calcium binds to troponin
(specifically troponin C) to allow a shift of tropomyosin complex towards actin filament, and consequently
allows exposure of the actin binding site and spur muscle contraction. Approximately 60% of mutations
can occur in the myosin-binding protein C and troponins, which are implicated in familial hypertrophic
cardiomyopathy.
S o la ro , R . J . e t a l. C ir c R e s 1 9 9 8 ;8 3 : 4 7 1 -4 8 0

C o p y r i g h t 1 9 9 8 A m e r ic a n H e a r t A s s o c ia t io n

A better question to ask though is how the troponins and tropomyosin play a role in the regulation of actinmyosin interactions. Troponins C, T, and I are formed together to yield a regulator complex along actin.
Troponin C binds calcium ions and initiates a macromolecular rearrangement. Cardiac troponin I is
different than in sketal muscle. When TnC binds to TnI, it allows an opening up of the region. This
molecule will open up slightly. There will be amino acids that will have tnI bound, and a hydrophobic
pocket will be yielded from the movement of tropomyosin. In states of diastole, the tropomyosin will be
down, overlapping the binding sites. In states of systole, the regulatory complex will rearrange and move
the tropomyosin and expose the myosin-binding sites.

Differentiate between troponin subunits.

Troponin
Subunit
I
C
T

Description
Binds to actin in thin myofilaments to hold the actin-tropomyosin complex is place. Because of it, actin can bind to myosin in
relaxed muscle.
Contains four calcium binding EF hands. It also contains an N lobe and a C lobe. The C lobe serves a structural purpose and
binds to N domain of Troponin I. The C lobe can bind either to calcium or magnesium ions. The N lobe, which only binds to
calcium ions, is the regulatory lobe and binds to the c domain of Troponin I after calcium binding.
It binds to tropomyosin, interlocking to for a troponin-tropomyosin complex. It helps orient it on actin.

Identify two of three putative mechanisms for cooperativity.

Muscle has very important cooperative functions. Cooperative means that tension is greater than number
of calcium binding sites. This implies that there are more binding sites. Cooperativity is defined as tension
development is greater than the number of calcium binding sites, in the case of cardiac muscle. Proposed
mechanisms is as follows:
1. Cross bridge formation between actin and myosin increases the affinity of troponin for calcium
ions. There is an increase of troponin C for calcium. I you have a movement of proteins that is
transmitted to the next troponin complex does not explain the different amounts of activation
even though there is the same amount of calcium.
2. Binding of a cross bridge increases the rate of formation of neighobring cross bridges and that
multiple cross bridges can activn activation even in the absence of calcium ions. Potentially, you

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3.

can move the tropomyosin to the neighboring region to allow myosin to act even if calcium is
absent.
End-to-end interactions between adjacent troponin and tropomyosin.

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