Muscle Function

Question 1

Students will be able to describe the innervation of skeletal muscle with emphasis on the origin of the motor nerve, the neurotransmitter released and the receptor activated.

Answer 1

Origin: Ventral region of spinal cord
NT: acetylcholine
Receptor: Nicotinic Receptors

Question 2

a. Excitation Contraction signaling in skeletal muscle involves the following:

Answer 2

i. Motor neurons releasing acetylcholine
ii. Acetylcholine interactions with skeletal muscle nicotinic receptors to:
iii. Increase sodium permeability and depolarize skeletal muscle
iv. Skeletal muscle depolarization causes activation of L calcium channels (dihydropyridine receptors)
v. Calcium entry into muscle releases calcium from intracellular storage sites (sarcoplasmic reticulum) via calcium-induced calcium release (ryanodine receptors)
vi. Elevated intracellular calcium concentrations result in calcium binding to troponin C
vii. Calcium binding to troponin C releases inhibition of actin-myosin interactions
viii. Myosin heads then contact actin to create muscle shortening and force generation, provided energy in the form of ATP is present

Question 3

Students will be able to precisely define the mechanism by which actin and myosin interact including the role of ATP, ADP and phosphate in each step of binding, power generation, and detachment of myosin from actin.

Answer 3

Myosin has bridges that can attach to actin and pull actin fibers toward the center of the sarcomere

1. Myosin bridges have an ATP binding site, as well as, an actin-binding site
2. Cleaving the ATP to ADP and Phosphate results in a conformational change in the myosin head to place it at a 90o angle instead of a 45o angle
3. Release of the phosphate causes the angle of the head to revert to 45o (power stroke of muscle)
   a. ADP is released during this phase
4. Binding of ATP allows the myosin head to release from actin and the process is repeated

Question 4

Relaxation

Answer 4

i. If actin and myosin are allowed to interact in the absence of ATP, the actin & myosin remain attached (rigor mortis)
ii. Relaxation of the muscle requires sequestration of calcium
1. This allows the troponin-tropomyosin complex to resume its inhibition of actin myosin interactions
2. Calcium sequestration requires energy
3. It is accomplished by Calcium pumps (Ca ATPases) in the sarcoplasmic reticulum
iii. Once calcium is sequestered and actin and myosin no longer interact, the muscle returns to its resting length but can be stretched easily

Question 5

i. Amyotropic lateral sclerosis (Lou Gehrig’s Disease)

Answer 5

involves degeneration of motor neurons

Question 6

ii. Lambert-Eaton syndrome

Answer 6

is caused by autoantibodies against Calcium channels in motor neurons resulting in an inability to release acetylcholine

Question 7

Botulism

Answer 7

prevents acetylcholine release by cleaving synaptic associated proteins (SNAPs)

Question 8

i. Myasthenia gravis

Answer 8

is caused by autoantibodies against nicotinic receptors in skeletal muscle (autoimmune disease)

Question 9

i. Malignant hyperthermia

Answer 9

is caused by a mutation of the ryanodine receptor allowing excessive release of calcium, usually triggered by anesthetics

Question 10

Duchenne’s muscular dystrophy

Answer 10

i. A mutation in dystrophin, a skeletal muscle support protein,

Question 11

4. Length-Tension relationships in skeletal muscle

Answer 11

a. The amount of force generated by a muscle is directly proportional to the number of actin-myosin crossbridges per cross-sectional area
b. Thus muscles work best when there is considerable overlap between actin & myosiniv.
If the sarcomere is shortened more than 2.0 µ, because actin filaments can bump into each other, compression pressures oppose contraction etc
v. If sarcomere is shortened to 1.7µ, the myosin actually contacts the Z line and resists further shortening (rapid drop-off of force)

Question 12

5. Force-velocity relationship

Answer 12

a. Muscles contract most rapidly when there is no load on the muscle
b. If the muscle needs to work against a load, it first must shorten enough to stretch the tendon that it attaches to
i. The tendon represents an elastic element (called series elastic component) that must be pulled out (like a spring) before something can be moved
c. If the load on the muscle is constant, the contraction is termed isotonic
d. If the load is larger than the muscle’s ability to move it, the contraction is termed isometric
i. The muscle contracts enough to pull the tendon taut but does not actually move the bony attachment

Question 13

type I fibers

Answer 13

i. Slow twitch fibers are type I
1. The distinction in these muscles is a slower myosin ATPase enzyme
2. These are in high proportions in distance runners or in postural muscles such as the soleus
3. They contain a lot of myoglobin, resulting in the designation “red fibers”
4. They need the myoglobin because they require lots of oxygen to maintain contractions

Question 14

type II fibers

Answer 14

ii. Fast twitch fibers are type II
1. These are in high proportions in extraocular muscles of the eye
2. They have a faster myosin ATPase
3. They are termed white fibers (less myoglobin)
4. These muscles are adapted for anaerobic metabolism

Question 15

6. Types of contractions

Answer 15

a. Concentric
i. Muscle contracts resulting in shortening
1. Typical biceps curl in weightlifting
b. Eccentric
i. Muscle lengthens while attempting to shorten
1. Run down a hill
2. Much more damage to muscle with this type of contraction (really sore afterwards)

Question 16

Cardiac

Answer 16

i. Also striated
ii. Gap junctions between cells allow easy dissemination of electric impulses
iii. Differ from skeletal muscle:
1. Cardiac muscle has autorhythmicity
a. Does not require innervation to contract
b. Innervation simply slows or accelerates the contraction
2. Cardiac muscle is more dependent on Calcium-induced calcium release to elevate intracellular calcium concentrations

Question 17

Smooth muscle

Answer 17

ii. Contraction is not controlled by troponin or tropomyosin
1. It is initiated by calcium interacting with a calcium-dependent myosin light chain kinase
iii. Often has autorhythmicity, such as in intestinal muscle
1. Frequently contractions controlled by nerve or hormonal factors

Question 18

Efferent nerves from the spinal column:

Answer 18

1. Virtually always release acetylcholine (sympathetic, parasympathetic, somatic)
2. The acetylcholine virtually always interacts with a nicotinic receptor (postganglionic nerve, adrenal medulla, skeletal muscle)

Question 19

Anticholinesterases

Answer 19

Potentiate contraction
useful to treat myasthenia gravis
a. Neuromuscular junction – anticholinesterases contract skeletal muscle (nicotinic) because they increase acetylcholine concentrations in the vicinity of the nicotinic receptor (i.e., outside the somatic nerve)
(Neostigmine, Pyridostigmine, Edrophonium)

Question 20

Neostigmine

Answer 20

Potentiate contraction
(prostigmin tablets or injectable) - stimulates nicotinic receptors
1. quaternary ammonium
2. administration - oral (15 mg) or parenteral (0.5 mg i.m. or s.c.)
3. use is for myasthenia gravis (also will increase acetylcholine concentrations at muscarinic receptors to treat abdominal distension or atony of detrusor muscle)

poorly absorbed from the gut; used more in hospitalized patients

Question 21

Pyridostigmine (Mestinon, Regonol)

Answer 21

Potentiate contraction

used in myasthenia gravis or to reverse competitive neuromuscular antagonism; can be used prophylactically to prevent actions of nerve gases (tabun, soman)

Question 22

Edrophonium

Answer 22

Potentiate contraction

Tensilon injectable)

1. administered parenterally (1 to 2 mg i.m.)
2. used to diagnose myasthenia gravis (vs. cholinergic crisis) and in treating paroxysmal supraventricular tachycardia
3. increases strength in a myasthenic crisis and decreases strength in a cholinergic crisis
4. nicotinic receptor has a unique property in that excessive stimulation of nicotinic receptors desensitizes organ to further stimulation (principal behind a cholinergic crisis)

Question 23

Anticholinesterase toxicity

Answer 23

i. SLUDGE (sweating, lacrimation, urination, diarrhea, GI distress, emesis)

Question 24

d-tubocurare

Answer 24

Competitive agents such as d-tubocurarine- jaw > eyes > limbs > diaphragm fail to contract; anticholinesterases reverse block - physostigmine, neostigmine, etc.

major action to paralyze skeletal muscle; hypotension; decrease GI motility; depolarizing agents release K+

Question 25

mivacurium

Answer 25

competitive blocker

major action to paralyze skeletal muscle; hypotension; decrease GI motility; depolarizing agents release K+

Question 26

succinylcholine

Answer 26

succinylcholine depolarizes end plate of muscle- chronic Na+ influx causes depolarization; fasciculations precede flaccid paralysis

major action to paralyze skeletal muscle; hypotension; decrease GI motility; depolarizing agents release K+

Depolarizing agent
Myasthenics are resistant and anticholinesterases potentiate
Short duration of action because of rapid metabolism (butyrylcholinesterase)
Has some muscarinic and ganglionic nicotinic agonistic properties - can constrict bronchioles
Releases histamine
Can produce malignant hyperthermia -treat with calcium antagonist, dantrolene
Usually used for tracheal intubation to prevent aspiration of gastric contents; succinylcholine is preferred for this because of its rapid action
Avoid in burn patients (burned muscle increases the concentration of nicotinic receptors resulting in excessive potassium release in response to succinylcholine)

Question 27

botulinum toxin

Answer 27

Paralyze with inhibitors of acetylcholine release

Question 28

dantrolene

Answer 28

Prevent contraction and malignant hyperthermia with dantrolene (calcium chelator)

inhibits Ca2+ release from sarcoplasmic reticulum by blocking the Ryanodine receptor (Calcium-induced calcium release)

Question 29

Drug Interactions

Answer 29

Ether, halogenated anesthetics, streptomycin, tetracycline enhance competitive block
Anticholinesterases- antagonize competitive blocker but potentiate a depolarizing blocker
epinephrine and norepinephrine - slight ability to reverse competitive blockade

Question 30

Treatment of muscle spasm

Answer 30

Botulinum toxin A (Botox)
Injected into region of spastic muscle
Prevents acetylcholine release by cleaving proteins (SNAP25) necessary for acetylcholine exocytosis (reviewed in TRENDS in Molecular Med. 11: 377-381, 2003)
Effects last approximately 3 months
Used to treat spasms of eye, throat, skin and other muscles (urinary bladder)
Also used to suppress sweating
Botulinum toxin is most potent (lethal) toxin known (1-5 ng/Kg i.v. in humans is the lethal dose)
This may be of major concern in bioterrorism
Actually 8 different serotypes of botulinum toxin- only have antisera to three (A, B and E)