Biochemistry

of Cardiac Muscle
Arta Farmawa7

Despopoulos, Color Atlas of Physiology 2003 Thieme

All rights reserved. Usage subject to terms and conditions of license.

A. Structure and function of heart, skeletal and smooth muscle

Smooth muscle

Structure and
function

Cardiac muscle (striated)

Skeletal muscle (striated)

Motor
end-plates

None

None

Yes

Fibers

Fusiform, short (< 0.2 mm)

Branched

Cylindrical, long (< 15cm)

Mitochondria

Few

Many

Few (depending on muscle type)

Nucleus per fiber

Multiple

Sarcomeres

None

Yes, length < 2.6 m

Yes, length < 3.65m

Electr. coupling

Some (single-unit type)

Yes (functional syncytium)

No

Sarcoplasmic
reticulum

Little developed

Moderately developed

Highly developed

Ca2+ switch

Troponin

Troponin

Pacemaker

Calmodulin/caldesmon
Some spontaneous rhythmic activity
(1s1 1h1)

Yes (sinus nodes ca.1s1)

No (requires nerve stimulus)

Response to stimulus

Change in tone or rhythm frequency

All or none

Graded

Tetanizable

Yes

No

Yes

Work range

Length-force curve
is variable

In rising
length-force curve

+ 20

Response
to stimulus

Spike

mV 0
Spontaneous
fluctuation

20

Potential
Muscle
tension

60

60

100
0

200

400

600
ms

Absolutely
refractory

+ 20
mV 0
20

40

(see 2.15E)

Relatively
refractory

At peak of
length-force curve (see 2.15E)
Absolutely
refractory

+ 50
mV 0
50
100

100

200

300 400
ms

10

59

Plate 2.10 Muscle types, motor unit

20

ms

30

Basic Contractile Unit of Muscle

LA
RA
LV
RV

FIGURE 1

(Left) The attachment of a skeletal muscle. Contractions of the muscle result in

movement of the arm, thus lifting the weight. (Center) Relaxation of cardiac muscle (top) allows
the heart to fill with blood. Contraction of cardiac muscle (bottom) reduces the size of the
ventricals, thus expelling blood into the pulmonary artery and the aorta. (Right) A small artery
whose wall is comprised mostly of smooth muscle. Relaxation (top) and contraction (bottom) of
the muscle increases and decreases, respectively, the diameter of the artery, thus altering the
resistance to blood flow.

Many cells can change shape and/or move about. For

characteristic of muscle and are arranged in filamen

Cardiac Muscle

Present only in the heart

Cells are striated and branching
Ends of cells are joined by
communica7on jungc7ons that
allow the cells to contract as a
unit

Specity of Cardiac Metabolism (1)

The heart is one of the most ac7ve 7ssue in the
body
Myocardial func7on depends on a ne
equilibrium between the work the heart has to
perform to meet the requirements of the body &
the energy that it is able to synthesize and
transfer in the form of energy-rich phosphate
bonds to sustain excita7on-contrac7on coupling
Heart muscle is highly oxida7ve 7ssue
To support high rates of cardiac power,
metabolism is design to generate large amount of
ATP by oxida7ve phosphoryla7on

Specity of Cardiac Metabolism (2)

Under basal aerobic condi7ons, 60% of energy comes
from FFA and triglycerides, 35% from carbohydrates,
5% from amino acids an ketone bodies
Mitochondrial respira7on produces more than 90% of
energy
Mitochondria occupy ~30% of cardiomyocyte space.
>95% of ATP forma7on comes from oxida7ve
phosphoryla7on in mitochondria
~ 60-70% of ATP hydrolysis is used for muscle
contrac7on, ~30 - 40% for the sarcoplasmic re7culum
(SR) Ca2+-ATPase and other ion pumps

Specity of Cardiac Metabolism (3)

Cardiac muscle diers in several important
respects:

the cardiac ac7on poten7al is not ini7ated by neural

ac7vity specialized cardiac muscle 7ssue in the
heart itself ini7ates the ac7on poten7al, which then
spreads directly from muscle cell to muscle cell.
Neural inuences have only a modulatory eect on
the heart rate
the dura7on of the cardiac ac7on poten7al is quite
long the full force of cardiac contrac7on results
from a single ac7on poten7al. The force of
contrac7on is not the same for every beat of the heart
and can be modulated by the cardiac nerves

Exita7on Originates Within

The Heart Muscle Cells (1)
Two broad types of cells are found:
Contrac7le cells
the cells of the working myocardium and
cons7tute the bulk of the muscle cells that make
up the atria and the ventricles
An ac7on poten7al in any one of these cells leads
to a mechanical contrac7on of that cell
an ac7on poten7al in one cardiac muscle cell will
s7mulate neighboring cells to undergo an ac7on
poten7al, such that ac7va7on of any single cell
will be propagated over the whole heart

178

Excitation is Conducted from Cell to Cell Through Gap Junctions

Sarcolemma

T tubule

Mitochondrion

Sarcoplasmic
reticulum

Mitochondrion
Cisterna

Z line
I band

A band

Sarcotubular
network

FIGURE 3

Ultrastructure of a contractile cell. A contractile cell in the heart is very similar to skeletal muscle in
its basic cellular organization. (Modified from Katz AM. Physiology of the heart. New York: Raven Press, 1992.)

transverse aspect of the intercalated disc is filled with

structures called desmosomes. The desmosomes make
strong mechanical attachments between the cells and
transmit the force of contraction. The transverse aspect
as well as the longitudinally oriented region of the

potential in one muscle cell is propagated to adjacent

muscle cells via direct electrotonic propagation across the
gap junctions. The gap junctions cause every cell in the
heart to be electrically coupled to its neighboring cells
and that is what causes the heart to behave like a single

for every twitch (for a review, see Chapter 7). The

action potential is so short in skeletal muscle that a
single action potential generates an insignificant
amount of force. Usable force can only be achieved
by stimulating the fiber repeatedly with a train of
neural discharges (temporal summation). Individual
motor units can be stimulated within a muscle as a
further means of control. Cardiac muscle differs in
several important respects. First, the cardiac action
potential is not initiated by neural activity. Instead,
specialized cardiac muscle tissue in the heart itself
initiates the action potential, which then spreads
directly from muscle cell to muscle cell. Neural
influences have only a modulatory effect on the heart
rate. Second, the duration of the cardiac action
potential is quite long. As a result, the full force of
cardiac contraction results from a single action potential. The force of contraction is not the same for every
beat of the heart and can be modulated by the cardiac
nerves. Finally, all cells in the heart contract together
as a unit in a coordinated fashion with every beat.
This chapter examines the electrical properties of the
cardiac muscle cells. We begin by looking at the
different types of cells in the heart. The properties and
ionic mechanism of cardiac action potentials, the
processes of excitationcontraction coupling, and the
regulation of the heart rate will be explained.

the initiation or propagation of action potentials but

have little mechanical capability. The principal conductile cells are indicated in Fig. 1. Of critical importance is
the sinoatrial (SA) node. The SA node (sometimes called
the sinus node) lies in the right atrium near the vena
cava. SA nodal cells generate spontaneous action

Exita7on Originates Within

The Heart Muscle Cells (2)

Conduc7le cells

specialized muscle cells

that are involved with
the ini7a7on or
propaga7on of ac7on
poten7als but have
licle mechanical
capability
FIGURE 1 Structure of the conduction system of the heart.
Structures colored blue are those responsible for generating and
propagating the wave of excitation that leads to contraction of the
heart. (Modified from Katz AM. Physiology of the heart. New York:
Raven Press, 1992.)

Mechanical
energy

B. Regeneration of ATP
1 Cleavage of creatine phosphate
Reserve:
ca. 25 mol
per g muscle

ADP

CrP
Creatine
kinase

Glycogen

Reserve:
ca. 100 mol/g muscle

Blood
glucose

Liver
1
ATP

Glucose-6-P
1
ATP

anaerobic

1. Dephosphoryla7on of
crea7ne phosphat
2. Anaerobic glycolysis
3. Aerobic oxida7on of
glucose and facy acids

2 Anaerobic glycolysis

Net gain:
2 mol ATP/mol glucose
(3 mol ATP/mol glucose-6-P)

Long-term high
performance

4
ATP
Increase in lactic acid

2pyruvic acid

2pyruvate +2H

Drop in pH

2lactic acids

2H++2 lactate

Broken down
in liver
and heart

3 Oxidation of glucose
2
Acetyl-CoA

Total net gain:

36 mol ATP/mol glucose

6O2

aerobic

Three routes of ATP

regenera7on:

Short-term
peak performance

ATP

Cr

Energy Supply for Mus

Plate 2.17

Heat

H2O

6CO2

Krebs
cycle

Respiratory
chain

34
ATP

Despopoulos, Color Atlas of Physiology 2003 Thieme

Endurance sport

73

Fuel U7liza7on in Cardiac Muscle

Normal condi7on

The heart primarily uses facy acids (6080%), lactate, and glucose
(2040%) as its energy sources
Ninety-eight percent of cardiac ATP is generated by oxida7ve
means; 2% is derived from glycolysis.
The lactate used by the heart is taken up by a monocarboxylate
transporter in the cell membrane that is also used for the trans-
port of ketone bodies
Ketone bodies are not a preferred fuel for the heart, because the
heart prefers to use facy acids
Lactate is generated by red blood cells and working skeletal muscle.
When the lactate is used by the heart, it is oxidized to carbon
dioxide and water, following the pathway lactate to pyruvate,
pyruvate to acetyl-coA, acetyl CoA oxida7on in the TCA cycle, and
ATP synthesis through oxida7ve phosphoryla7on. An alterna7ve
fate for lactate is its u7liza7on in the reac7ons of the Cori cycle in
the liver

Chapter 5 Fundamentals of Human En

+i

Muscle Cell
Muscle
Gycogen

Muscle
Protein

Pyruvate

Glucogenic
Amino Acids

Blood

iVLii>
>V`VVi

Lactate
Alanine

Glucose

Pyruvate
Lactate

Glycogen

Liver

Figure 5.16 /i
VViiiii}Viv>V>iii>i`
v>ViVi/}Vi}iVVi>>V>L`>iiii

}V}iiViiViviv`> /

>}>>i
VV

Fuel U7liza7on in Cardiac Muscle

Ischemic condi7on
When blood ow to the heart is interrupted, the heart switches to
anaerobic metabolism
The rate of glycolysis increases, but the accumula7on of protons (via
lactate forma7on) is detrimental to the heart.
Ischemia also increases the levels of free facy acids in the blood oxygen
is reintroduced to the heart, the high rate of facy acid oxida7on in the
heart is detrimental to the recovery of the damaged heart cells
Facy acid oxida7on occurs so rapidly that NADH accumulates in the
mitochondria a reduced rate of NADH shucle ac7vity an increased
cytoplasmic NADH level, and lactate forma7on
Facy acid oxida7on increases the levels of mitochondrial acetyl CoA,
which inhibits pyruvate dehydrogenase, leading to cytoplasmic pyruvate
accumula7on and lactate produc7on pH drops more dicult to
maintain ion gradients across the sarcolemma
ATP hydrolysis is required to repair these gradients, which are essen7al for
heart func7on

Interregula7on of facy acid and

carbohydrate oxida7on
The primary physio-logical
regulator of ux through
PDH and the rate of
glucose oxida7on in the
heart is facy acid oxida7on
PDH ac7vity is inhibited by
high rate of FA oxida7on
via an increase in
mitochondrial acetyl-CoA/
free CoA and NADH/NAD+
which ac7vates PDH kinase

Interregula7on of Facy Acid and

Carbohydrate Oxida7on
Inhibi7on of FA
oxida7on increases
glucose and lactate
uptake and oxida7on
by:
1. decreasing citrate
levels and inhibi7on of
PFK
2. lowering acetyl CoA
and/or NADH levels in
the mitochondria

Keton Body Metabolism

During starva7on or poorly controlled diabetes the
heart extracts and oxidized ketone bodies (-
hydroxybutyrate and acetoacetat)
Low insuline and high facy acids # ketone bodies.
Ketone bodies become a major substrate for
myocardium
Ketone bodies inhibit PDH (inhibi7on of glucose
oxida7on) and facy acid -oxida7on

Some Aspects of Myocardial

Biochemistry of Heart Failure
Heart failure reduces the capacity to
transduce the energy from foodstu into ATP.
In the advanced stage of HF a
down regula7on in FA oxida7on,
increased glycolysis and glucose oxida7on
reduced respiratory chain ac7vity

Excita7on-Contrac7on Coupling is Accomplished

by Calcium Ions
Three pools of Ca2+ are important to the cardiac muscle
cell:
in the extracellular uid
in the SR
in the cytoplasm

In skeletal muscle, ac7on poten7als on the T tubules

electrically s7mulate the SR to release calcium. That is not
the case in cardiac muscle however. Rather the small
amount of Ca2+ entering the cell through the L-type calcium
channels actually triggers the release of the sequestered
Ca2+ within the SR
SERCA (sarco-endoplasmic re7culum Ca2+-ATPase) removes
Ca2+ from the contrac7le pool and pumps it into the SR.
When enough Ca2+ is removed from the cytosol, the muscle
relaxes

myocyte and their individual functions in controlling

K conductance through the action potential are
complex. A detailed description of these is beyond
the scope of this chapter.

SR to release calcium. That is not the case in cardiac

muscle however. Rather the small amount of Ca2
entering the cell through the L-type calcium channels
actually triggers the release of the sequestered Ca2

Simplified model of calcium handling in cardiac muscle cells. EX, Na-Ca2

exchanger. See text for details.

FIGURE 8

Cardiac Muscle
Contrac7on Mechanism

Contrac7on and Relaxa7on Cardiac Muscle

Contrac7le Reserve (1)

Considerable contrac7le reserve is normally available to meet
varia7ons in circulatory demand (involves changes in the
cytosolic calcium transient and/or myolament responsiveness
to calcium), is regulated by the following factors:
Frank-Starling rela7onship
an increase in myocyte length (brought about
by increased ventricular diastolic volume) increases contrac7le force
The major underlying mechanism is increased myolament
responsiveness to calcium, but length- dependent release of
autocrine/paracrine factors may also be involved
At a cellular level, the FrankStarling response is thought to be
maintained in human heart failure, though myocyte stretch may be a
limi7ng factor in a heart that is dilated and s7

Contrac7le Reserve (2)

Heart rate
an increased heart rate enhances contrac7le force primarily as the
result of an increase in sarcolemmal calcium inux per unit 7me, and
consequent increased loading of the sarcoplasmic re7culum with
calcium
The failing human heart exhibits a greatly blunted forcefrequency
rela7onship

Autonomic control
sympathe7c ac7va7on, involving catecholamine release, has both
posi7ve inotropic and chronotropic eects via -adrenoceptors. These
ac7ons are antagonized by parasympathe7c release of acetylcholine
The inotropic eect of -s7mula7on results from an increase in the
intracellular calcium transient caused by increases in ICa and
sarcoplasmic re7culum calcium release

Contrac7le Reserve (3)

Autonomic control
-s7mula7on also accelerates relaxa7on by s7mula7ng
sarcoplasmic re7culum calcium uptake, promo7ng faster
dissocia7on of calcium from the myolaments, and accelera7ng
cross-bridge cycling

Autocrine/paracrine regula7on
cardiac myocytes are in ini7mate contact with the endothelial
cells of the coronary microvasculature, which are ideally
posi7oned to sense and transduce local signals (e.g. mechanical
forces, hypoxia, hormones) in the perfusing blood
Coordinated release of factors such as nitric oxide, endothelin-1
and angiotensin II by these endothelial cells allows local
regula7on of contrac7le func7on. Some of these factors are also
generated by cardiac myocytes themselves, par7cularly in
pathological senngs

in pathological settings.

 



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Nitric oxide
has direct ac7ons on cardiac myocytes, independent of
its vasodilator eects. These include:
accelera7on of myocyte relaxa7on and reduc7on in
diastolic tone, resul7ng from a reduc7on in myolament
calcium responsiveness
small posi7ve inotropic and chronotropic eects
damping down of responses to -adrenergic s7mula7on

Endothelin-1
a potent vasoconstrictor and posi7ve inotrope that
acts by increasing both the calcium transient and
myolament calcium responsiveness. Endothelin-1
may s7mulate release of angiotensin II, which has
similar ac7ons and may therefore amplify the eects
of endothelin-1

The Cardiac Enzymes

Crea7ne kinase
A specic CK isoenzyme
(CK-MB) is a more specic
indicator of cardiac muscle
damage than total CK, but
CK-MB is not completely
specic for myocardium

Apartate amino
transferase
Is a less sensi7ve index of
myocardial damage

Lactate dehydrogenase

Cardiac Marker Non Enzyme

Myoglobin

A haem-containing protein present in cardiac and skeletal

muscle, rises early following myocard infarct but not
spesic test

Troponin

Possible to detect infarc7ons that are orders of magnitude

smaller than those detectable with other cardiac marker

Homocysteine

Accumula7on of homocysteine in toxic level arterial

damage

Plasminogen Actvator Inhibitor (PAI-1)

Fibrinoly7c hypofunc7on as an atherogenic factor