MUSCLE

Fox Chapter 12 (plus references to chapters 5, 7 & 15)

How muscle works molecularly has been a real success story in cell-molecular biology.

Cell structure

Fig. 12.1
Skeletal ("striated" = striped) muscle cell ("fiber" = cell) 10- 100 microns [micro, 10 to the minus 6. meters] (huge) and long (from tendon to tendon)
There are smaller units within fiber called "myofibrils" (1-2 microns in cross section)
Thus 1000-2000 myofibrils/fiber

Fig. 12.6a&b
Sarcomeres are units along the length of myofibrils
Interestingly, the striped (striated) pattern of myofibrils is in register for all the myofibrils in the fiber giving the whole muscle fiber a striated appearance.
Within the myofibrils are the filaments
Actin - G (globular) polymerizes to F (filamentous) actin - the thin filament
Myosin - (2 heavy chains and 4 light chains) - the thick filament
I-band (isotropic - light), A-band (anisotropic, dark) based on actin and myosin, see figure

here is a picture from our histology course, but watch out because the arrows for A, I, and H do not point accurately

Muscle proteins

Fig. 12.8 like last figure
Z disc where actins are joined in the middle of the actins
M line in the middle of the myosin
A (anisotropic)= where myosin is
I (isotropic) where actin is but not myosin
H (helle) (lighter) where there is myosin but not actin
This figure shows titin a gigantic protein that is elastic

"Clinical application" box on p. 356
Muscular dystrophy (Duchenne) X-linked recessive (sex-linked), affects boys
Lethal by age 20
"Dystrophin" protein associated with muscle cell membrane, binding cytoskeleton with extracellular matrix.

Sliding filaments

AFHuxley & RNiedergerke, 1954, Nature
173 971-973
Interference microscopy of living muscle fibers

HHuxley & J Hanson, 1954, Nature 173
973-976 (back to back!)
Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation

Contraction of muscle was well-described in 1958 (H.E.Huxley, The contraction of muscle, Scientific American, Nov. 1958); he is not related to the other Huxleys, Thomas (zoologist and advocate of Darwin), Thomas's grandson, biologist Julian, Julian's brother Aldous, author of Brave new world, and Julian's and Aldous's half brother, Nobelist Andrew F. Huxley whose other work (with Hodgkin) we covered earlier.

Fig. 12.9a&b
Sliding filament explanation of muscle contraction

Fig. 12.21
The length tension curve shows that the optimum is when there is good overlap without the actin colliding (note, there will be an important difference for heart muscle.)

Involvement of ATP

Fig. 12.10
picture myosin as a boat rowing through a sea of surrounding actin molecules.

Fig. 12.12
Interestingly ATP binding unhooks myosin from actin. This can be remembered by thinking about rigor mortis (box p. 348) - a "stiff" in a detective show - has been dead long enough so that ATP has run out and actin and myosin are locked together. ATP -> ADP and a phosphate added to the myosin and this is like the rower back-stroking to get ready to take another power stroke. When the phosphate gets kicked off of the myosin, the myosin and actin bind, followed by the power stroke

Involvement of Ca2+

Fig. 12.14
Ca2+ ions are released to make muscle contract (explained later)
tropomyosin on actin
troponin has a Ca2+ binding site like calmodulin
Ca2+ binding to troponin pulls tropomyosin off of actin's binding sites for myosin

The neuromuscular junction

Fig. 12.3
here is a similar picture from our histology course of the neuromuscular junction
Action potential from nerve opens channels (nicotinic acetylcholine receptors) at "synapse" called the neuromuscular junction. (Notice that the nerve branches.)
This is a big "synapse" and it works.
Here is a transmission electron micrograph of a portion of a neuromuscular junction. Note the folds, increasing the area on the muscle cell. Note the space with electron density in the cleft. Note the numerous vesicles.

Bernard Katz shared the 1970 Nobel prize for using the quantal nature of transmission at the neuromuscular junction. The quanta are individual vesicles. The neuromuscular junction is like any synapse except bigger and easier to study. This information could fit equally well here, in the muscle lecture, or in the synapse lecture (but that was already crowded with Nobelists.

Box in Chapter 7 on page 184
Table 15.10
autoimmune diseases
Myasthenia gravis is an autoimmune attack on nicotinic receptors
Muscle weakness
Here's a picture I found on the web of the eyelid droop
Give AChE (neostigmine) inhibitor neostigmine to ameliorate symptoms

Table 7.5
nicotine is an agonist. there are pharmacological antagonists (curare, a plant alkaloid from Clondodendron tomentosum)
Important for mechanisms of muscular relaxatants used in surgery (like succinylcholine)
Must relax muscles in surgery but must prove that anesthesia is adequate.

The spinal motor neuron

Clinical applications Box on p. 380
Amyotropic Lateral Sclerosis (Lou Gehrig's disease affects spinal motor neurons)
some cases familial led to identification on chromosome 21
coper/zinc Super Oxide Dismutase (SOD1) reduces oxygen radicals
some famous baseball personalities, Lou Gehrig set consecutive games record until broken by Cal Ripken Jr.
Lou Gehrig's farewell speech

Fig. 12.4
(relative to the aforementioned "nerve branches") Motor units
(how many muscle cells per motor neuron)13 eye, 1730 calf

The muscle cell's action potential

Fig. 12.16
Then action potential goes down muscle cell. But cell is too big. So transverse tubules (T tubules) get action potential into cell at numerous locations (for each sarcomere and for each myofibril). Proximity with a specialized smooth endoplasmic reticulum called the sarcoplasmic reticulum causes release of Ca2+.
That "proximity" involves actual interaction of the types of Ca2+ channels in transverse tubules and in sarcoplasmic reticulum.

Fig. 12.19
1 - 1 spike, tetanus for sustained
Note that eventually, fatigue sets in.
A few years ago, in General physiology lab, one of the lab groups obtained the result shown Here. the result when tetanus was obtained by increasing the amplitude of stimulation.

In summary:

ACh to synapse Ecxitation to spike
Final common pathway - motor neuron carries integrated information from nervous system
action potential in membrane and t-tubules, t=transverse
Ca++ release from sarcoplasmic reticulum (ER)
T at A-I junction in Skeletal muscle but it is at the z line in cardiac muscle and in frog skeletal muscle

Types of skeletal muscle:

Difference obvious in turkeys
Fast twitch, strong, anaerobic, white meat
Slow twitch, enduring, aerobic, dark meat
capillaries (hemoglobin), myoglobin, cytochromes in mitochondria
can alter with training
It is possible to stain, in this case for ATPase, to show mixed muscle cells in a muscle (dark is slow, aerobic).

Metabolism:

Fig. 12.24
phosphocreatine (creatine phosphate [backup, battery]) makes ATP using phosphpcreatine kinase

Fig. 12.22
muscle uses glucose and fatty acids (from plasma)
and glycogen and triglyceride (from muscle)

Glycogen -> (glycogenolysis) -> glucose
Overall, 1 glucose can give up to 38 ATP's, a few from glycolysis and the rest from the mitochondrion
Without oxygen, make ethanol (yeast) or lactate (lactic acid).
Anaerobic glycolysis is used to deliver ATP quickly but wastefully (squandering glucose).
Make ATP's but need to regenerate NAD+ [from NADH] to make.

Fig. 5.6
Lactic acid contributes to fatigue in muscle and oxygen debt, and the liver eventually reconverts.
Anaerobic cellular "respiration" is needed in times of extreme exertion because the heart (cardiac output) is the limiting factor in delivery of oxygen to muscle.
Lactic acid is also made by bacteria in yogurt, sour cream, and cheese.

Fig. 16.37
Hemoglobin off-loads oxygen to myoglobin

Monitoring muscle stretch

Fig. 12.27b
remember reflex from synapse lecture
knee-jerk reflex - tap patellar ligament, spindle (stretch receptor, alpha motoneuron to muscle)
gamma motor neuron goes to nuclear chain fibers (intrafusal muscle) to set tone on spindle
sensory fiber wraps around nuclear bag fiber

Smooth muscle

In an undergraduate physiology lab, a piece of rabbit gut is connected to a force transducer. Rhythmic contractions are monitored. Drugs like atropine (see autonomic lecture) slow motility, and this is why it is in anti-diarhea medications. When I was a kid, a teaspoon of some terrible tasting stuff called paregoric cured a belly ache right away, but you can't get paregoric (tincture of opium) any more.

Fig. 12.35 b & c
smooth muscle - arterioles, gut, uterus - involontary, autonomic
actin and myosin are arranged differently (striations helped in sliding filament theory)

Fig. 12.36
Ca2+ comes across cell membrane, not from SR
activates myosin light chain kinase, phosphorylation
phosphorylation (and dephosphorylation) of myosin regulates cross-bridge

Fig. 12.37
regulated by autonomic neurons with varicosities and synapses enpassant
in single unit, autonomic activates then it passes from cell to cell
in multiunit, need to activate each cell

Dr. Fisher is our muscle expert, and he teaches a course in exercize physiology

Exam questions from 2004 - 2008 related to this outline

Shortage of what chemical leads to rigor mortis?

ATP

What is an intrafusal motor fiber?

presets stretch on spindle's stretch receptor

What does a kinase do to a protein?

phosphorylates it

Suppose you are stimulating the nerve to the gastrocnemius muscle. What would BoTox do to the response?

decrease it

When does a spinal motor neuron cause a hyperpolarization at the end plate of a striated muscle cell?

never

In the middle of the dark A band is a lighter H zone. Why is it lighter?

because there is myosin but no actin

What ion, critical to muscle contraction, binds troponin, pulling tropomyosin myosin's binding site on actin?

Ca2+

What is the ATP binding protein in muscle?

Myosin

During exercise, what does the conversion of phosphocreatine to creatine achieve?

makes ATP

During anaerobic metabolism in muscle, what is pyruvic acid converted to?

lactic acid

The sarcoplasmic reticulum calcium release channel is closely related with what channel on the transverse tubule?

a different calcium channel

Several diagrams in your book referred to skeletal muscle fibers as "extrafusal muscle fibers." Why?

to distinguish them from intrafusal in muscle spindle

What happens to the relationship of actin and myosin when ATP binds?

they unbind

While exploring the Amazon, you are shot with a blow-gun dart of curare. What would that do to you?

paralyze

For the monosynaptic knee-jerk reflex, what cell does the sensory neuron of the spindle's stretch receptor synapse onto?

spinal motor neuron

Why is Duchenne muscular dystrophy more common in boys than in girls?

because the mutation is X-linked

What does "striated" mean in the context of striated muscle, and why was the fact that muscle is striated important in developing the sliding filament theory?

striped, helped Huxleys infer actin & myosin properties

Why would it be easier halfway up a chin-up than starting from a position of fully extended arms?

optimal overlap of actin and myosin as opposed to too little overlap

Heart muscle does not follow the length-tension relationship of skeletal muscle. Why is this important?

Fuller ventricle is capable of generating more force of contraction

What treatment would alleviate some of the muscle weakness from autoimmunity to the nicotinic channel?

anti-acetylcholinesterase like neostigmine

Lowering extracellular Ca2+, Katz did his Nobel Prize winning work as he converted the end plate potential to miniature end plate potentials elicited by "quanta." What is the physical appearance of the quantum he witnessed physiologically?

vesicle

The channel carrying the action potential in the T (transverse) tubule is closely linked to what important component in muscle contraction?

sarcoplasmic reticulum (the Ca2+ channel)

What prevents the myosin head from binding actin in striated muscle when a contraction is not called for?

tropomyosin

How would motor units differ in the extraocular muscles (responsible for eye movements) vs. calf (gastrocnemius) muscle?

fewer muscle cells per neuron in muscles for finer movement

Which cell is damaged in ALS (amyotropic lateral sclerosis, Lou Gehrig's disease)?

spinal motor neuron

In smooth muscle, what can phosphorylated myosin light chain do that the unphosphorylated protein cannot?

bind actin

Gamma fibers preset the stretch receptor by causing what specific type of fiber to contract?

intrafusal (or nuclear chain)

What is created from glycogen by glycogenolysis?

glucose (or glucose 6-phosphate)

What type of cell uses phosphocreatine (creatine phosphate)?

striated muscle

If there is lactic acid formation, oxygen debt, and creation of only a few ATPs per glucose molecule, what is this type of metabolism called?

anaerobic glycolysis

Varicosities on autonomic nerves are used to control what kind of muscle?

smooth muscle

Without Ca2+ what does tropomyosin block?

Binding sites on actin for myosin

What transmitter and transmitter receptor are used at the motor end plate?

Acetylcholine nicotinic

Why would curare, by itself, be a poor choice for anesthetizing a patient for surgery?

It is a paralytic, not an anesthetic

In what way does a graph of tension as a function of time look different for complete vs. incomplete tetanus?

Bumpy for incomplete

In what way does smooth muscle's myosin light chain kinase (MLCK) substitute for striated muscle's troponin-tropomyosin complex?

Phosphorylation of myosin allows cross-bridges

Here is a partial list of the proteins of striated muscle: actin, myosin, troponin, tropomyosin. Name another.

titin, dystrophin, myoglobin

What happens specifically when either phosphate or ADP (you pick one) comes off the myosin?

myosin binds to actin and power stroke is taken

One sarcomere goes from the z-line (z-disc) to (where)?

the next z line

How would the H zone look in the biceps at the bottom of a chin-up vs. at the top?

H big at bottom, small at top

T-tubules (transverse tubules) are best known for their channels for which ion?

Ca2+

If you are not active at the time, after a meal, "in times of plenty," glucose is imported into muscle and converted into what?

glycogen

What would happen to the end plate potential elicited by one spike in the motor neuron if the extracellular concentration of Ca2+ in the vicinity of the neuromuscular junction were reduced?

become smaller, become ), 1 or several miniature potentials

By what mechanism does neostigmine help a patient with myasthenia gravis?

increase acetylcholine to better stimulate what is left of the nicotinic receptors

What is the limiting factor that requires the body's muscles to go to anaerobic glycolysis for extreme exertion?

heart's ability to deliver O2

What is the X-axis (abscissa) for the oxyhemoglobin dissociation curve, the graph that shows that myoglobin has a higher affinity for oxygen than hemoglobin?

partial pressure of O2 in mm Hg

What is a nuclear chain fiber used for?

intrafusal muscle to preset stretch receptor

Why can't myosin bind to actin unless it's supposed to?

tropomyosin blocks the sites on actin for myosin binding

Which muscle protein changes configuration, power stroke and back stroke, for muscle contraction?

myosin

Put in order from large to small three alternative, anatomical, words for muscle cell, the subcomponents that make up the cell, and the muscle proteins that make up these subcomponents.

cell=fiber, myofibril, filament=protein

How does the conversion of ATP to ADP affect creatine?

creatine becomes creatine phosphate

What is the function of gamma fibers and their connection to nuclear chain fibers?

preset stretch for stretch receptor

Under the influence of Ca2+-calmodulin, what protein in smooth muscle gets dephosphorylated?

myosin light chain kinase

Give one way the neuromuscular junction is distinguished from the typical synapse in the nervous system.

larger, only excitatory

In terms of the muscle proteins, why is the muscle weaker when it is full length or stretched?

less actin myosin overlap

In terms of muscle proteins, why does the length of the H (helle) zone vary with muscle length?

myosin without overlap with actin

Where is the lactic acid that is built up in muscle taken care of?

liver

Ca2+ channels in the t- (transverse-) tubules are in contact with Ca2+ channels in what subcellular structure.

sarcoplasmic reticulum

What famous drug paralyzes skeletal muscle by blocking the muscle membrane receptor?

curare

What is the cause of the disease of muscle weakness in which nicotinic receptors are lacking?

autoimunity to nicotinic

What enzyme is deficient in familial cases of Lou Gehrig's disease?

Super Oxide Dismutase

How does the oxyhemoglobin dissociation curve explain the offloading of oxygen when blood arrives at muscle?

myoglobin's curve is to the left

Striated muscle's tension (strength) depends on its length. Out of A-band, I-band, and H-zone, which ones change size (as a function of muscle length) and which do not?

A stays the same, I and H would change

Why did they call one muscle protein "dystrophin?"

before they knew anything about function, they identified it as deficient in muscular dystrophy

Calcium ions would indirectly regulate whether ATP is used in muscle. Why wouldn't ATP replace ADP if calcium had not done what it does?

myosin needs to be able to bind actin for that ATP cycle to be able to run

What happens to tropomyosin to allow (or not) muscle contraction?

it exposes (or blocks) binding sites for myosin on the actin

Sir Bernard Katz won his Nobel Prize for demonstrating the quantal nature of transmission at the neuromuscular junction. What happened when he lowered the extracellular Ca2+?

fewer (for instance 0, 1, or 2) vesicles (his quanta) were released

From the depolarization at the nicotinic receptors of the motor end plate, an action potential (using activated Na+ channels) moves down the sarcolemma (muscle cell membrane). That triggers what other channels? (Your answer could state what ion or what cellular component.)

calcium in both t-(transverse)-tubules and sarcoplasmic reticulum

In human surgery (and in animal research), you cannot tolerate muscle movement. Why do you need to be particularly careful about using muscle relaxants?

you need to be certain the patient (or animal) is sufficently anesthetized because paralysis would prevent any communication of distress

What is the significance of myoglobin's curve being to the left of hemoglobin's curve (on the oxyhemoglobin dissociation graph)?

hemoglobin would offload oxygen to muscle

In contrast with the type of cell an alpha motor neuron innervates, what does the gamma neuron connect to?

intrafusal muscle in the muscle spindle

Intracellular Ca2+ is exquisitely orchestrated. In contrast with the calcium binding protein of striated muscle, what is the calcium binding protein of smooth muscle?

calmodulin

Striated muscle has an optimum length, and it's strength (tension) drops off when it is longer or shorter. In what way is the ventricular myocardial muscle strikingly different?

The fuller (more stretched) the ventricle, the more forceful the contraction

Why is a corpse at a crime scene referred to as a "stiff?"

When ATP runs out, actin stays bound to myosin

Why would neostigmine ameliorate the condition of myasthenia gravis?

Shortage of nicotinic channels is somewhat overcome if there is more ACh

What cell is deficient in Lou Gehrig's disease (ALS=amyotropic lateral sclerosis)?

Spinal motor neuron

What are varicosities with respect to control of smooth muscle?

NE is released not so much by synaptic terminals but by many swellings along the axon


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this page was last revised 6/25/09