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Muscle Physiology

Voluntary - have control over them

Involuntary - part of the Autonomic Nervous System - We do not have control over them e.g. cardiac
muscles or visceral smooth muscle in small intestine.
Striated - distinctive cellular structure
Smooth - spindle shaped and looks very smooth
Skeletal Muscles:
Muscle cell (muscle fiber) is multinucleated (has more than one nucleus).
Sarcolemma is the plasma membrane surrounding the single Muscle Fiber.
Sarcomere is the repeating cellular structure within the myofibril.
Sarcoplasmic Reticulum - same as endoplasmic reticulum. Its main function is to store calcium.
Sarcoplasm - everything else within the Sarcolemma except contractile apparatus (same as cytoplasm)
Muscle cell has numerous mitochondria because we need energy (ATP) for muscle contraction.
Transverse Tubules (T Tubules) - is the continuation of Sarcolemma = sarcolemmal invaginations. Action
potential in muscle will travel on outer membrane continue to travel to T Tubule etc which we will
later learn.
A skeletal muscle consists of a bundle of long fibers running parallel to the length of the muscle.
Looking within each bundle we see many Muscle Fibers (myofibers). Each Muscle Fiber is a single
Skeletal Muscle Cell. Skeletal Muscle Cells are multinucleated. They are innervated by a single nerve
ending and has a cell membrane called the Sarcolemma.
Within each skeletal muscle cell (Myofiber) there are many smaller units called Myofibrils. The
Myofibril is responsible for striated appearance of skeletal muscle and generates the contractile force
of skeletal muscle.
All skeletal muscles are innervated by somatic motor neuron which release ACh as the
neurotransmitter at neuromuscular junction.
The proteins in the Myofibril that generates contraction are polymerized Actin and Myosin.
Actin polymerizes to form thin filaments and myosin form thick filaments. The striated appearance
(sarcomere) is due to the overlapping arrangement of bands of thick and thin filaments in Sarcomeres.
A myofibril is composed of many Sarcomeres aligned end-to-end. Each sarcomere is bound by two Z
lines. Thick filaments (myosin) are not attached to Z line.
Myosin are held in place by a protein called Titin. Titan anchors thick filament myosin to -Actin Z disc
Z line is composed of Alpha Actin Protein which holds Actin filaments together.

Rate of Actin to Myosin in sarcomere is 2:1.

I band = isotropic band. The region of the Sarcomere composed only of thin filament (Actin) is referred
to as I band. It is the light band. Z line bisects I band.
A band = anisotropic band. It is equal to the full length of the thick (myosin) filament. It is the zone of
Actin/myosin overlap. It does not change the length during contraction.
H Zone = is the central area of the (only) myosin filament that contains no cross bridges.
M Line = is found inside/middle of the H Zone. (M Line is in the center of the myosin)
Z Line or Z discs form the end boundaries of the sarcomere and anchor the Actin filaments. (Z line is in
center of Actin)
When muscle contract, H band is reduced, I band is reduced but A band remains of the same size.
There is no change in A band because myosin molecule do not change length. M line more or less
remains the same whereas Z line to Z line distance decreases.

Anchoring Sarcomere:
Dystrophin - connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix
through the cell membrane. If we don't have Dystrophin, then we may suffer from muscular dystrophy.
Actin: is a thin filament, Actin has myosin-binding sites that allows us to have muscle contraction.

Tropomyosin: lies between the groves of Actin helices. It covers the Myosin-binding sites so
myosin cannot attach. It blocks the myosin binding sites at rest

Troponin: It is a protein that has 3 subunits:

Troponin I (TnI) has strong affinity for Actin. It Inhibits contraction
Troponin C (TnC) has high affinity for Calcium ions
Troponin T (TnT) has a strong affinity for Tropomyosin

Nebulin: runs the length of the Actin filament and regulates its length during sarcomere

Myosin = (thick) filaments

Myosin is a long protein that is composed of tail and a globular head structure

S1 Globular Head = It is the portion of the myosin that binds to Actin (It has Actin-binding sites).
It also has enzymatic activity that hydrolyzes ATP to gives us energy from muscle contraction.

Myosin is arranged in tail to tail fashion so that all the tails are in the center and heads pointing
out. Central Bare Zone is the region where we have all the tails (no head).

Excitation-Contraction Coupling Mechanism:

AT NMJ, we have an alpha motor neuron that comes down to specified location on muscle fiber. When
alpha motor neuron innervations comes down to these pocket regions at motor end plate where there
is a small synaptic cleft. Within that cleft we have subneural cleft where we get more imagination in
the membrane. ACh is the only NT for NMJ.
At motor end plate, we have vesicles of ACh which are aggregated and almost attached to a structure
called Dense Bar. At these dense bars there are calcium channel, that causes the release of NT ACh
from the vesicles when calcium enters the neuronal cell. In postsynaptic membrane (muscle
membrane) we have Nicotinic ACh receptor (nAChR - they are ionotopic ligand gated sodium channel they are not voltage gated sodium channel) which will get activated.
Sodium will initially come through nicotinic ACh receptor and will cause a local depolarization which
will then activate voltage gated sodium channel which will then fire an AP.
Endplate potentials sum to threshold level depolarization.
End plate potentials (EPPs) (sometimes called "end plate spikes") are the depolarizations of skeletal
muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular
1. Resting Membrane Potential - @ -90mV
2. Depolarization is going to make conformation change in DHP receptor. DHP receptor will change
its shape and by doing so it turns on a channel that allows calcium to move out of the
sarcoplasmic reticulum (which is the storage area of Ca2+) into the Sarcoplasm. This channel is
known as Ryanodine Receptor. So, DHP receptor activates Ryanodine receptor which is
essentially an ion channel.
3. Ca2+ binds to TnC causing a conformational change in the Troponin complex.
4. Inhibitory effect of TnI is removed as Tropomyosin filament (bound to TnT) is pulled away
from the myosin binding sites.

5. This exposes the Myosin-binding site on Actin and causes the myosin head to be attached to the
Actin and sliding can occur. (At rest the myosin binding site in Actin is blocked by Tropomyosin).
Attachment of myosin cross bridges occurs:

ATTACHMENT: Myosin has ATPase activity so it hydrolyzes ATP (Myosin ATPase hydrolyzes
ATP) and when it does it gives energy. Myosin is now energized by the hydrolysis of ATP
and binds to the myosin-binding site on Actin.

PULLING: Hydrolysis of ATP in previous step leaves Myosin with ADP and Pi. Now ADP and
Pi is released and so energy is released as well and that causes myosin head to shift.
This is known as the power stroke. Power Stroke is not the hydrolysis of ATP but it is the
release of ADP and Pi that causes head to shift.

DETACHMENT: Now we have a shifted Myosin head that is attached to the Actin and has
no energy. Thus, binding of a new ATP molecule is necessary for the release of Actin by
myosin head. (Myosin head detaches as ATP binds to it)

REACTIVATION: Now ATP is hydrolyzed and the new cycle begins.

6. Termination of Contraction:

Ca2+ is removed from the Sarcoplasm and actively pumped back into the t-tubules.
Calcium rises only briefly during contraction.

When cell membrane repolarizes, DHP goes back to its regular conformation thereby
inhibiting or blocking Ryanodine receptor. Now Ca2+ ATPase Pump will take calcium and
bring it back to the SR. The protein phospholamban acts as a break on this pump. Ca2+
is also pumped out of the cell by a Na+/Ca2+ pump in the Sarcolemma

Calsequestrin helps with the reuptake. Calsequestrin is a calcium-binding protein of the

sarcoplasmic reticulum. The protein helps hold calcium in the cisterna of the
sarcoplasmic reticulum after a muscle contraction, even though the concentration of
calcium in the sarcoplasmic reticulum is much higher than in the cytosol.

7. Relaxation occurs. Relaxation is mediated by repolarization (lack of ACh) and other pumps that
help bring Ca2+ level down.

A = Spontaneous release of Ach - it is random and happens and causes small change in AP. This is known
as MEPPM (miniature endplate potential) change in voltage by a single release of Ach. But MEEP was
not enough to reach the threshold.

B = Now a little bit ACh is released and then threshold was crossed and AP was fired.
C = Alpha Motor neuron is stimulated but no Ach is released

Muscle Mechanics
Types of Skeletal Muscle Contraction:

Isometric even though tension increases total muscle length remains constant (Iso-metric). We
take a muscle and attach it to a set device that prevents it from changing its length and
measure the amount of force generated in it. Muscle is not allowed to change its size but it
creates a force

Isotonic even though muscle shortens, there is no change in tension. (Iso-tonic). For example,
we are lifting something and muscle is shortening but it is maintaining the same amount of

Tetanus a force (or tension) plateau occurs when a series of stimuli are applied rapidly.
Increasing stimulus frequency leads to more Ca2+ on the Sarcoplasm. More contraction
generated, with less recovery. Tetanus occurs when there is no more fluctuation in force. It's a
sustained contraction.

Summation - increased force (or tension) when a second stimulus (action potential) is applied
before complete relaxation.

A = single muscle twitch. One action potential (a single stimulus) releases ACh but doesn't hit
threshold. Calcium is released and gone (calcium taken back to SR).
B = 8 stimuli per second. Calcium is released, started taken back to SR but 0.8 seconds sec later
we sent another stimulus telling Calcium to come out. Calcium ATPase pump still trying put calcium
back to SR when we sent another stimulus . This process is overpowering the ability of Calcium
ATPase pump to return all the Calcium to SR. This causes accumulation of Calcium in the
Sarcoplasm. Also, chance to recover is decreasing (trough are decreasing in size). Summation of
calcium - the more calcium you have around the greater the force of contraction will be Summation.
C = 50 stimuli per second. Calcium concentration accumulates and very quickly max out thereby
and thereby generating sustained contraction - tetanus.

Fatigue is due to loss of ACh from alpha motor neuron. We have limited amount of ACh prepackaged in vesicle. When we empty out the terminal we experience fatigue. Continued neural
stimulation depletes Ach from the -motor neuron causes fatigue.

Preload - load placed on a muscle before it contracts (or load placed on a muscle in relaxed state)
Afterload - is the force muscle must develop to shorten and lift the load

1 - unloaded muscle
2 - preloaded muscle - stretching a muscle before contraction. Preload increases Passive tension.
3 - After load - we are pushing/contracting against a load . E.g. lifting a chair .
4 - Muscle is preloaded and we are trying to lift something as well. So it is already preloaded and
we are after loading (lifting the load).

Length-Tension Relationship:

Force (tension) that a muscle can develop is dependent on the overlap of the thick and thin
filament (sarcomere length); Related to the number of binding sites available for cross bridge

Our sarcomere has an optimal length where we have overlap and we can move those Actin
filaments closer together. If muscles filaments are too close, we have a condition A. If we pull
that sarcomere out we get an optimal length which is B & C. D happens when we stretch our
muscles to the point that there is no overlapping in the actin/myosin - this would be a pulled
muscle and cannot contract (since for contraction we need actin/myosin attachment and they
are separated). Optimal length of sarcomere is 2.2 micrometer and we want most of muscle in
that shape.

There is a relationship between amount of stretch and the amount of force a muscle could

Blue Line is Passive Recoil Force - (what happens to tension in the sarcomere when we stretch
it). We want to have it at the optimal length (resting) of 1.0 (1 times normal is 1 x 2.2 = 2.2).
So when we have our muscle at optimal length (Resting Length) we have maximum contractile
force. Contractile force which is generated by actin/myosin and is measured as active muscle
tension. So at rest, our muscle have maximum active muscle tension.

Red Dotted Line - Active muscle tension - force generated by contractile elements (actin and
myosin cross bridge cycle)

Active force + passive force gives us total muscle tension. In case of a muscle that is at
optimum length, it can generate a lot of active force. So at optimal length, total force would
comprise pretty much of Active force.

If we stretch that muscle beyond optimum length we are making it difficult for actin and
myosin to interact with each other. Thus active tension starts to drop. So for example, at 1.2
times normal, passive tension has increased but active tension has decreased.

At extreme length, we will see we have all passive tension and no active tension.

The above graph is also an example of isometric contraction. We have fixed the muscle length, and we
are measuring changes in tension.

Force-Velocity Relationship:

Velocity of contraction: increasing the load on a muscle slows contraction

Fmax (zero velocity) is the load just big enough to produce an isometric contraction (no
external shortening).

Vmax is the extrapolated maximal velocity of unloaded muscle shortening

Isotonic contraction - e.g. if we are lifting a lighter object (light load) e.g. cell phone then it
would not take a lot of force to do that. We would directly go to isotonic contraction. This
happens very quickly. Its velocity of contraction is very fast.

Isometric Contraction e.g. lifting up the podium or very heavy. Before we even lift it, we have
isometric force generated in our arm. So we are trying to lift that, applying force but it is not
moving and finally after enough force is applied it moved. So the muscle size was the same but
the tension was increasing. In isometric contraction, velocity of contraction is slow in lifting
heavy load.

Types of Whole Muscle:

Whole muscles are made of many fibers arranged as motor units. They vary in duration of
isometric contraction: optimized for function

1. Fast (Type II) e.g. Ocular

2. Slow (Type I) e.g. Soleus
Slow oxidative fiber (Type I) - red

Smallest diameter less force

Slower ATPase activity and slower velocity of contraction

Aerobic cellular respiration to produce ATP

More myoglobin and blood supply

Longer to fatigue

Fast Oxidative-Glycolytic fiber (Type IIa)

Intermediate diameter intermediate force

Moderate ATPase activity and moderate velocity of contraction

Aerobic cellular respiration and Glycolysis to produce ATP

Less myoglobin and less blood supply

Fast Glycolytic fiber (Type IIb) - white

Largest diameter and force

Fast ATPase activity and velocity of contraction

Glycolysis to produce ATP
Least myoglobin and blood supply

Biceps has all three types of fibers and they use it selectively depending on what contraction is
needed. Muscle carry out different functions at different times

Smooth Muscles:
Not striated, but smooth under light microscope. Spindle-shaped, smaller than skeletal muscle.
Less mitochondria than skeletal and so have much less energy requirement. They can contract a
greater force using less energy. Much more efficient.
Long and spindle-shaped arranged in bundles or sheets.
Very thin and long. They don't have T tubule system. Instead they have long invaginations called
Caveolea. Caveolea are located near SR. Caveolea: increase surface area, associated sarcoplasmic
Actin attached to dense bodies. Dense bodies act as junction point for actin. It is not nearly as
Calmodulin is the regulatory protein (similar to TnC)
There is no defined repeating structure/sarcomere.
Less SR than striated muscle
No Troponin complex and have a different coupling mechanism. There is Tropomyosin but they have a
different function.
Ca2+ for activation comes both from extracellular fluid and SR.
Fast (T-type) and Slow (L-type) Ca2+ channels exist in cell membrane.

Adrenergic Alpha and Beta receptor types exist in the cell membrane.

Alpha receptors cause contraction

Beta receptors cause relaxation

Cholinergic receptors cause contraction

Multi-unit smooth muscle

Discrete, single independent muscle cell. They will only be found under autonomic neural innervations.
Smooth Muscles are part of autonomic Nervous System - Involuntary Control. Parasympathetic
Autonomic is rest and digest. Major neurotransmitter for parasympathetic nerve is ACh. Sympathetic
Autonomic Nervous System is fight or flight. Major NT for sympathetic nerve is Norepinephrine.
Example: Ciliary and iris muscles (control pupil), vas deferens
Unitary Smooth Muscle
Muscle fibers contracting as a single unit - working together. Many cells working together because they
are connected by gap junction. Gap junction allows movement of calcium through them and therefore
form Syncytium (in sync).
They also have Spontaneous pacemaker activity - some of them spontaneously contract.
They are regulated by Hormonal, local mediator and neural regulation.
Example: Visceral smooth muscle (GI tract, bladder), uterus, vascular (arteries)
Filaments difference compared to skeletal muscle:
Actin (more) and myosin proteins similar to skeletal muscle
No Troponin complex
Contraction mechanism similar to skeletal muscle
Actin filaments attached to dense Bodies (similar to Z-disc)
Side-polar myosin. It's not just tail to tail arrangement but myosin is arranged in different ways.
Excitation-Contractile Mechanism
There are many ways in which we can increase intracellular calcium in smooth muscle

Electrochemical - Voltage gated Calcium Channels. Depolarization of membrane open voltage

gated calcium channel that allows calcium to enter the cell.

Pharmochemical: Calcium Induced Calcium released (CiCIr). Extracellular Ca2+ enters and
releases stored Ca2+ in the SR. it activates Ryanodine receptors (calcium channels in SR).

Mechanochemical coupling: Ligand or Hormone or NT binding to a receptor. It causes a signaling

reaction that increases IP3. IP3 has receptors on SR which opens up the calcium channel and
calcium will increase in cytosol

(In skeletal muscle, ACh is the only NT that causes depolarization which open DHP and Ryanodine
receptors. In smooth muscles we have a lot of ways)
Depolarization causes Innervated cells to open membrane Ca2+ channels and Ca2+ enters the cell.
Activation also stimulates the formation of Inositol-triphosphate (IP3) which stimulates the release of
Ca2+ from intracellular stores (SR).
Ca2+ binds with calmodulin.
The Ca2+calmodulin complex activates Calmodulin kinase which then activates MLCK. Myosin light
chain kinase (MLCK) the phosphorylates the myosin light chain cross bridges allowing them to attach to
If we remove the phosphate of myosin light chain,, it goes in to Latch state. In latch state we can have
sustained contraction and can be in that state for a long time. Even though MLCK loses its phosphate
but myosin head would stay there and contracted. We later need to put phosphate back to continue
the process. So, Latch Mechanisms is process whereby myosin light chain is dephosphorylated while
head attached. It results in sustained contraction without using much energy.
Myosin phosphates allows relaxation. Phosphates will remove phosphate from MLCK and deactivate it.
Relaxation of smooth muscle:
Relaxation is caused by decrease in calcium. If we want to relax, we decrease calcium in Sarcoplasm.

Calcium Pump in SR can pump calcium back into SR storage

On Sarcolemma we have Na/Ca exchanger and it works by secondary active transport. Na/K
pump bring K in and Na out. Now, we can bring that sodium back in and drive calcium back out
using secondary active transport

We have another Calcium ATPase on the plasma membrane (similar to one that is on SR) can
also pump Calcium outside,

Myosin phosphatase that removes phosphate from MLCK and deactivates it.

Increasing cAMP levels inhibits MLCK CAMP is a cell signaling molecule and if you increase their
concentration, it will inhibit MLCK.

Increasing cGMP levels activates phosphotases.

Hyperpolarization by Ca2+ activated K+ channels will decrease smooth muscle contraction.

Smooth Muscle NMJ

As we said there are two types of smooth muscle cell: Multi-unit smooth muscle and Unitary Smooth
Multi-unit are innervated individually by very simple NMJ called Varicosities.
In case of Unitary/Single unit - we have varicosities but it just secrete NT in one area because they are
all connected.
Comparison: Skeletal muscle has a very well defined NMJ. Smooth muscle NMJ is not very well defined
as they have varicosities.
NMJ in smooth muscle release ACh or NE. NE is going to bind to receptors and those receptors increase
or decrease signaling molecules including cAMP, cGMP, IP3
Sympathetic Norepinephrine receptors are - alpha adrenergic and beta adrenergic. Beta adrenergic
upon binding with NE increase cAMP and cause smooth muscle to relax. NE will also bind to Alpha
adrenergic receptors it would increase IP3 and would cause it to contract.

Action Potential of Smooth Muscle:

AP of smooth muscle is very different. Action potentials vary in the different smooth muscle cells
(resting potential: -50-60 mV)
In Multi-unit cell, even the smallest depolarization will cause contraction.
In Unitary Smooth Muscle we have: Spike Potential, Plateau. Slow Waves
Spike Potential - is just like what we saw in skeletal muscle. Voltage gated Sodium causes
depolarization, and that leads to increase in calcium and lead to smooth muscle contraction. The
difference is, the latent period is a lot longer than skeletal. Latent period is the time between
depolarization and contraction.
Plateau - Calcium comes in and causes a plateau. Cardiac muscle has AP similar to this
Slow Waves - exhibit pacemaker activity - do it on all on its own. There are unitary smooth muscle cell
that will open up some sodium channels and they depolarize. There is nothing hormonal, neuronal,
chemical triggering this. If sometimes it does not depolarize then it would have slow waves.

Factors regulating Contraction:

Local Chemical Factors (relaxants): Good example is arteriole smooth muscle.

Lack of Oxygen

Excess Carbon Dioxide

Increased H+ ion concentration

Adenosine, K+, decreased Ca2+

You have an arteriole and around that we have unitary smooth muscle which is trying to regulate the
flow of blood and if it is constricted, then it will be a smaller size blood vessel, but of it is relaxed
then your blood vessel will get bigger and there will be a greater blood supply.
When we workout, Oxygen in our muscles go down, Carbon dioxide increases. CO2 increase cause an
increase in Hydrogen concentration. Contraction of Muscle requires ATP which is being used up and we
are left with ADP - so concentration of adenosine increases.
Hormones also regulates smooth muscle
Effects mediated by receptors present on muscle cell
Excitatory open Na +or Ca2+ channels to depolarize
Inhibitory close Na +or Ca2+ channels , open K+ channels to hyperpolarize
Many alter cAMP and cGMP levels to cause relaxation Phosphorylation which inhibits contraction.
E.g. oxytocin is a hormone which will stimulate smooth muscle contraction.
Cardiac Muscle
It has a defined sarcomere/repeating structure within muscle cell.
Cardiac Muscle cell are connected with each other via intercalated disc which act as a gap junction
location. Gap Junctions allow muscle cell to communicate with each other.
Desmosomes which are associated with gap junctions are made of intermediate filaments.
Cardiac muscle cell has a lot more mitochondria than skeletal. They perform efficient and rapid
contraction. They can respond to epinephrine and other chemical mediating factors. (They don't have
nicotinic receptors or anything. They are controlled predominately by NE and sympathetic autonomic
The Sympathetic system kicks in when there is a fight or flight response. The sympathetic
postganglionic neuron directly innervates the heart releasing Norepinephrine; and epinephrine
secreted by adrenal medulla binds to receptors on cardiac muscles. This increases the heart rate and
the force of contraction
Vagus Nerve is parasympathetic nerve that innervates heart and digestive system. It slows the rate of
heart contraction and increases digestive activity in intestine
Skeletal Versus Cardiac


Cardiac has pacemaker potentials autorhythmic, neural modulation


Skeletal requires a-motor neuron

Striations both have connected myofibril networks

Cellular connections


Cardiac muscle fibrils connected by intercalated disc

a. Electrical gap junctions syncytium contract together
b. Mechanical junctions desmosomes and adhereins hold cells together
c. Folded membrane which interlock


Skeletal single muscle units require separate stimulation to contract

Sarcoplasmic reticulum

Cardiac less developed than skeletal


Both have T-tubule network, cardiac larger

Mechanical energy cardiac has more mitochondria, glycogen and myoglobin

Repair skeletal has cells to repair, cardiac cannot repair

Excitation-Contraction Coupling:

Similar to skeletal and smooth muscle

Ca2+ from extracellular activated intracellular release

Phosphorylation regulation of relaxation

Electrochemical and pharmochemical coupling

Contraction dependent on the level of Ca2+

In skeletal muscle calcium come from SR only. In smooth muscle calcium comes from SR and CiCIr. In
Cardiac muscle, calcium comes from channels in plasma membrane CiCIr and also SR.
Cardiac Muscle is more similar to skeletal.

Phospholamban is a protein which when it is phosphorylated it increases the activity of the calcium
pump to store calcium in SR. It causes relaxation to occur fairly quickly.
Cardiac AP:
Action potential: resting membrane potential -80- to -90 mV

Plateau phase due to Ca2+ channel activation

Multiple K+ currents

Myocardium acts as a syncytium; all myocytes contract (as if it were a single motor unit). Recruitment
cannot occur.
Force of contraction can be modulated by other factors.
Similar ECC to skeletal muscle [AP from SA node, Ca2+ enters cell, CICR, large change in [Ca2+], cross
bridge attachment & cycling]
The rate and amount of Ca2+ binding to TnC can vary depending on conditions
Long in duration
Long refractory period (cannot be tetanized)
Phase 2 plateau due to inward Ca2+ current
Amplitude and duration of Phase 2 can be altered