Transcript rigidity electrical accessory

HKMU
FOM
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INTRODUCTION
-Current understanding of the
molecular events underlying muscle
contraction is embodied in the
sliding filament model of muscle
contraction.
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The model is applicable to smooth,
skeletal, cardiac, and other
contractile activity, including
mechanochemical events such as
single cell locomotion and receptor
endocytosis
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The biochemical characteristics and
biochemical basis of some common
pathophysiological states of muscle,
includE fatigue and rigor mortis
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Skeletal muscles comprise about
40% of the mass of the average
human body and are formed of
long multinucleate, cylindrical
cells called muscle fibers
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actin thin filaments and myosin
thick filaments are arranged to
form the myofilaments of a
sarcomere, continuing with the
formation of myofibrils from
many myofilaments
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The plasma membrane of muscle fibers is
known as the sarcolemma. Each muscle is
made up of bundles of these fibers, or cells,
embedded in a matrix of connective tissue
known as the endomysium.
The bundle of fibers with its endomysium is
surrounded by a more fibrous connective
tissue sheath known as the perimysium.
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The composite of the perimysium and its
contents is known as a fasciculus.
A complete muscle consists of numerous
fasciculi surrounded by a thick outer layer
of connective tissue known as the
perimysial septa
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The translation of contractile activity of
individual muscle fibers to anatomical
motion take place through this
continuous system of connective
tissues and sheaths.
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Within the sarcolemma is the sarcoplasm,
containing all the usual subcellular elements plus
long prominent myofibrils.
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Each myofibril is composed of bundles of
filamentous contractile proteins, some extending from
end to end in the cell.
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Myofibrils are the most conspicuous elements
in skeletal myofibers making up about 60% of
myofiber protein.
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A single myofibril is composed of many short
structural units, known as sarcomeres, which
are arranged end to end
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The proteins at the junctions between
sarcomeres form the Z line, and thus a
sarcomere extends along a myofibril from one Z
line to the next Z line ( Dermacation).
Sarcomeres are composed mostly of actin thin
filaments and myosin thick filaments.
Sarcomeres represent the minimal contractile
unit of a muscle
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It is the coordinated contraction and
elongation of millions of sarcomeres in a
muscle that gives rise to mechanical
skeletal activity.
Organization of Contractile Proteins
in Muscle
THICK FILAMENT:
Composed of hundreds of long, contractile myosin
molecules arranged in a staggered side by side
complex.
 THIN FILAMENT:
Composed of a linear array of hundreds of globular,
actin monomers in a double helical arrangement.
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SARCOMERE
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The unit of contractile activity
composed mainly of actin and
myosin and extending from Z line
to Z line in a myofibril.
Myofibril
End to end arrays of identical sarcomeres.
Myofiber
A single multinucleate muscle cell containing
all the usual cell organelles plus many
myofibrils.
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 Muscle
Organized arrays of muscle fibers.
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ORGANIZATION OF THE SARCOMERE
The organization of individual contractile proteins
making up a sarcomere is a key feature of the sliding
filament model.
Each sarcomere is composed of hundreds of
filamentous protein aggregates, each known as a
myofilament
TWO KINDS OF MYOFILAMENTS
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Are identifiable on the basis of their diameter
and protein composition
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Thick myofilaments are composed of several
hundred molecules of a fibrous protein known
as myosin
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Thin myofilaments are composed of two
helically interwound, linear polymers of a
globular protein known as actin.
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Proteins of the Z line, including a-actinin,
serve as an embedding matrix or anchor
for one end of the thin filaments, which
extend toward the center of sarcomeres
on either side of the Z line
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The Z line proteins often appear continuous
across the width of a muscle fiber and seem
to act to keep the myofibrils within a myofiber
in register.
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The distal end of each thin filament is free in
the sarcoplasm and is capped with a protein
known as b-actinin.
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The M-line, which is centrally located in
sarcomeres. Like Z line protein, the M line
protein aggregate acts as an embedding matrix,
in this case for the myosin thick filaments.
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Thick filaments extend from their point of
attachment on both sides of the M line toward
the two Z lines that define a sarcomere.
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During contraction and relaxation the
distance between the Z lines varies,
decreasing with contraction and
increasing with relaxation.
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The M line, with its attached thick
filaments, remains centrally located in the
sarcomere
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The thin and thick filaments retain their
extended linear structure
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Changes in sarcomere length are caused
by the thin filaments being pulled along
the thick filaments in the direction of the M
line.
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PROTEINS OF THE MYOFILAMENTS
The biochemical basis of muscle activity is
related to the enzymatic and physical
properties of actin, myosin, and the accessory
proteins that constitute the thin and thick
filaments
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The proteins of the thin and thick filaments can
be separated into actin, myosin, and accessory
proteins.
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The accessory proteins include b-actinin,
tropomyosin, troponin C and M line protein.
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Solubilized myosin molecules are long thin
(fibrous) proteins with a molecular weight of
about 500,000 daltons.
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Organization of Actin Thin Filaments
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Thin filaments are composed of many
subunits of the globular protein actin (42
kD) and several accessory proteins.
In thin filaments, Actin is polymerized into
long fibrous arrays known as F-actin
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A pair of linear F-actin arrays is helically
wound to form the backbone structure of 1
complete thin filament.
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In relaxed muscle, each tropomyosin molecule
covers the myosin binding sites of 7 G-actin residues,
preventing interaction between actin and myosin and
thus maintaining the relaxed state.
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The onset of contractile activity involves activating
troponin, the second accessory protein of thin
filaments
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Troponin is a heterotrimer attached to one end of
each tropomyosin molecule and to actin, physically
linking tropomyosin to actin.
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Conformational changes in the bridging molecule,
troponin, are responsible for moving tropomyosin on
and off myosin binding sites of actin and thus
regulating muscle contraction
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. One of the troponin subunits, troponin-C (Tn-C), is a
calmodulin-like calcium-binding protein.
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When Tn-C binds calcium, the whole troponin molecule
undergoes the conformational change that moves the
attached tropomyosin away from the myosin binding
sites on actin
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This event permits nearby myosin heads
to interact with myosin binding sites, and
contractile activity ensues.
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Events on the thin filament can be summarized as
follows: Prior to the appearance of free calcium in the
sarcoplasm, tropomyosin covers the myosin binding
sites on actin.
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The appearance of calcium in the sarcoplasm leads
to calcium binding on Tn-C.
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The resulting conformational changes in
troponin uncovers the myosin binding sites on
G-actin subunits.
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The exposed sites are then available to interact with
myosin headpieces.
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Removing calcium from the sarcoplasm restores the
original conformational states of troponin and
tropomyosin, preventing interaction between actin
and myosin and leading to the relaxed state
Myosin and the Power Stroke of
Contraction
- In a rested, non-contracting muscle,
myosin binding sites on actin are obscured
and myosin exists in a high-energy
conformational state (M*), poised to carry
out a contractile cycle
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The energy of ATP hydrolysis is used to drive
myosin from a low-energy conformational
state (M) to the high-energy state, as
illustrated in
Equation 1.
(M-ATP) <-----> (M*-ADP-Pi) Eqn. 1
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When cytosolic calcium increases and
myosin binding sites on actin become
available, an actomyosin complex is
formed, followed by the sequential
dissociation of Pi and ADP with conversion
of myosin to its low-energy conformational
state.
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These events are accompanied by
simultaneous translocation of the attached
thin filament toward the M line of the
sarcomere.
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The latter events, summarized in Equations 2
and 3 comprise the power stroke of the
contractile cycle
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Note that the energy of the power stroke is
derived from ATP, via ATP-driven
conversion of a low-energy myosin
conformational state to a high-energy
conformational state.
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A useful analogy is that ATP cocks the myosin
trigger and the formation of an actomyosin
complex pulls the trigger, releasing the energy
stored in cocking the trigger.
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(M*-ADP-Pi) + A <----> (M*-ADP-A) + Pi
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(M*-ADP-A) <-----> (M-A) + ADP
Eqn. 2
Eqn. 3
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At the end of the power stroke the actomyosin
complex remains intact until ATP becomes
available
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ATP binding to myosin is a very exergonic
reaction, with the result that ATP displaces
actin from the myosin head as indicated by
Equation 4.
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Thus it is often said that ATP is required for
muscle relaxation. It is important to note that in
relaxed muscle, myosin is in its high-energy
conformational state.
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Note that in Equation 4 the final product (M-ATP)
is also the first reactant shown in Equation 1,
completing the reactions of the contractile cycle.
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(MA) + ATP <------> (M-ATP) + A
Eqn. 4
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A diagrammatic illustration of the reactions
described in equations 1 through 4, as they
occur in muscle, is shown below
The process of reactions that occur leading to muscle contraction. A contractile cycle
begins with myosin in a high energy conformation depicted by A. The power stroke
begins with actin binding myosin in the A conformation and ends with formation of a low
energy actomyosin complex, depicted in C. The complex is broken by ATP binding (step
C to D) and the high energy conformation of myosin regenerated by ATP hydrolysis (D to
E). Notice that the conformation of myosin in A and E is identical.
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PROCESS OF REACTIONS THAT OCCUR LEADING TO MUSCLE
CONTRACTION.
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A contractile cycle begins with myosin in a high
energy conformation depicted by A.
The power stroke begins with actin binding myosin
in the A conformation and ends with formation of a
low energy actomyosin complex, depicted in C.
The complex is broken by ATP binding (step C to D)
and the high energy conformation of myosin
regenerated by ATP hydrolysis (D to E). Notice that
the conformation of myosin in A and E is identical.
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Regulation of Sarcoplasmic Calcium
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Events that stimulate muscle activity by
raising sarcoplasmic calcium begin with
neural excitation at neural muscular
junctions
Excitation induces local depolarization of the
sarcolemma, which spreads to the interior of
the myofiber
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T tubule depolarization spreads to the
sarcoplasmic reticulum (SR), with the effect
of opening voltage-gated calcium channels in
the SR membranes.
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This is followed by massive, rapid movement of
cisternal calcium into the sarcoplasm close to nearby
myofibrils.
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The appearance of calcium very close to the Tn-C
subunit of troponin results in the production of multiple
myosin power strokes, as long as the available
calcium concentration remains greater than about 1 to
5 micromolar.
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Muscle Relaxation: Normally, cessation of
contractile activity and a state of relaxation
follow electrical quiescence at the myoneural
junction.
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Then The sarcoplasmic membrane returns
to its resting electrical potential.
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Subsequently, sarcoplasmic calcium is
pumped back into the SR cisternae by an
extremely active ATP- driven calcium pump,
which comprises one of the main proteins of
the SR membrane.
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The cisternal surface of the SR
membrane also contains large
quantities of a glycoprotein known as
calsequestrin.
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Calsequestrin avidly binds calcium,
decreasing its concentration in the
cisternae, and thus favoring calcium
accumulation
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A final repository of sarcoplasmic calcium is the
mitochondrial matrix.
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Mitochondria have a remarkably active calcium
pump.
Under aerobic conditions this pump uses the energy
of electron transport to sequester calcium in the
mitochondrial matrix, in preference to the synthesis of
ATP
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SOURCES OF ATP FOR MUSCLE
CONTRACTION
1.Glycolysis
2.TCA.
3. ETC
4. creatine phosphate (CP)
5. and ADP.
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CP + ADP ------> Creatine +ATP
creatine kinase
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ADP + ADP -------> AMP + ATP
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Adenylate kinase
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Since tetanic stimulation raises sarcoplasmic
calcium and depletes ATP, the end result is a
highly contracted muscle with calcium bound
to Tn-C and no ATP available to resequester
calcium into the cisternae of the SR, nor to
break actomyosin cross-bridges
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The absence of ATP results in myosin
remaining in its low-energy conformational
state, with the result that new cycles of
muscle stimulation will result in only limited
ability of the muscle to generate contractile
activity.
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Muscles in this physiological state are said to
be fatigued.
Rigormortis
State of Muscle rigidity
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Lack of ATP
Determine Time of Death —Rigor
Mortis
Stiffening of the skeletal
muscles after death
 At death, skeletal muscles cannot relax.
 Without oxygen, calcium accumulates in
these muscles.
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Calcium is used by the body to signal muscle
contraction, this accumulation signals the
muscles to contract.
 The muscles become stiff.
 Rigor mortis starts in the head and works
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its way down to the legs.
Determine Time of Death —Rigor
Mortis
 2 -6 hours postmortem (after death), rigor
begins in the head
 12 hours postmortem, rigor is complete and
throughout the entire body
 15 -36 hours postmortem, the muscle fibers
begin to dissolve, and softening begins
(rigor mortis starts to end).
 36 -48 hours postmortem, rigor ends and is
relaxed throughout the entire body.
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Determine Time of Death —Rigor
Mortis
 2 -6 hours postmortem (after death), rigor
begins in the head
 12 hours postmortem, rigor is complete and
throughout the entire body
 15 -36 hours postmortem, the muscle fibers
begin to dissolve, and softening begins
(rigor mortis starts to end).
 36 -48 hours postmortem, rigor ends and is
relaxed throughout the entire body.
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Study questions
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1. Sources of ATP
2. Rigormortis
3.Role of calcium in muscle contraction
4.Biochemical events of muscle contraction