Muscle Flashcards
What are skeletal muscle cells called?
myofibers
- long and cylindrical
What are the dimensions of a typical myofiber?
50-100 micro meters in diamter
up to several cm long (2.5!)
How many nuclei do skeletal muscle cells have?
Up to hundreds
- too large to be controlled by a single nucleus
- nuclei may express different proteins depending on physical location (i.e. near motor neuron junction, near tendon)
- on periphery -> only central after injury
Describe typical cardiac muscle cell
single nucelus
shorter
small diameter
What is one distinguishing feature of cardiac muscle?
intercalated discs
What are the two functions of intercalated discs?
- physically links adjacent cells
2. contain gap junctions
What are gap junctions?
transmit electrical current
- necessary for synchronous cardiac contraction
Describe smooth muscle cells
2-5 micrometer diameter spindle shapes central nucleus not striated use same proteins to contract - different regulation
What are myofilaments?
actin and myosin complex
What are myofibrils?
bundle of skeletal muscle cells
What are myofibers?
single muscle cell
What are myocytes?
cardiac muscle cells
How is the unit of one sarcomere defined?
from 1 z line to the next z line
How is the sarcoplasmic reticulum related to myofibrils?
each myofibril is covers with its own sarcoplasmic reticulum
What protein forms the thin filament?
actin
What is the structure of actin in skeletal muscles?
F-actin (filamentous - v. globular)
double stranded
helical (intertwined strings of pearls)
1 micrometer long
What are the regulatory proteins bound to actin?
Tropomyosin
Troponin
How are tropomyosin and troponin bound to actin?
Tropomyosin - rod - binds length of 6-7 actin Troponin - bound to one end of tropomyosin (I,T, & C subunits)
What protein forms the thick filament?
Myosin
What is the structure of myosin?
6 proteins (3 pairs)
- 1 pair heavy
- 2 pair light
Each heavy chain has globular head
Pairs of heads staggered along length and around circumference of filament
1.6 micrometers long
How do tropomyosin and troponin control actin-myosin binding?
At Rest:
tropomyosin covers actin binding site
As Ca2+ levels rise:
troponin binds Ca2+
->induces conformation change in tropomyosin (they are bound together) -> actin binding site exposed
How does the myosin head bind to actin?
Once actin binding site is exposed “spring loaded” myosin binds - releases Energy on binding
=> immediately exerts 5pN force and shortens sarcomere by 8nm
How does myosin dissociate from actin?
Myosin remains bound to actin until ATP binds to myosin
- binding allows dissociation -> returns myosin to high energy state ready to bind actin again
How do muscles contract if each myosin-actin power stroke is only 8nm?
- sarcomeres contracting in series summate linerally ( can be hundreds to thousands)
- many myosin-actin cycles occur during each contraction
How quickly can a fast twitch myofiber contract?
20 times/sec
How quickly can a slow twitch myofiber contract?
5 times/sec
How is smooth muscle regulated?
No troponin
Calcium key regulator
Ca binds calmodulin -> binds CaM Kinase -> phosphorylates a light chain of myosin
Phosphorylated myosin binds to actin => generates force
How does smooth muscle contraction differ from skeletal and cardiac muscle contraction?
slower (up to 1 sec to generate full force)
Ca removed by pumps and Na-Ca exchangers
Kinases inactivated by removal of Ca
smooth muscle can remain in locked state-> contracting with myosin bound to ATP without consuming ATP
THINK OF THE SPHINCTERS!!!
What is the normal function of dystrophin?
One of the largest proteins
Links cytoplasm with extracellular matrix
- associates with globular actin (g-actin) beneath plasma membrane and with surface membrane
- Part of a protein complex
- Binds extracellular matrix molecules like laminin
What are 3 other important structural proteins?
Titin
Nebulin
Alpha-actinin
What is the function of Titin?
Links myosin thick filaments to Z-line => keeps myosin centered in sarcomere - large - myosin bound side inflexible - z line bound side extensible - contribute to passive tension in muscle
What is the function of nebulin?
Keeps thin filaments of actin organized
- large
- contribute to passive tension in muscle
What is the function of the alpha-actinin?
cross-links actin at the Z-line
What are the causes of familial cardiacmyopathy?
Single amino acid mutations
- in myosin heavy chain at head group (where it binds actin and where binds ATP)
- in troponin
Thicker left ventricle wall
How many places is each skeletal muscle innervated?
ONCE
exception: extra ocular muscles
Describe the action potential leading to the contraction of a skeletal muscle
Action potential in motor axon -> neurotransmitter ACh released -> ACh diffuses across synaptic cleft & binds AChR -> ion channel opens -> depolarization -> Na channels open
Propagates in both directions only takes 1-5ms
Contraction takes 50-100ms
What is the source of Ca2+ in skeletal muscle?
Sarcoplasmic reticulum
How is Ca2+ released from the SR?
AP transmitted by transverse tubule (t-tubule) -[Huxley and Taylor] ->
NO ELECTRICAL CONTINUITY HERE
(not enough charge to change capacitance)
-> AP is somehow translated from t-tubules to SR as induces Ca release
ECITATION-CONTRACTION COUPLING
What is the location where the SR contacts the t-tubule called?
terminal cisterna
Also: triad- electron dense - dark in EM proteins
Where is calsequestrin locatated? and what is its function?
in terminal cisterna
binds ~50 Ca++ each
What is the current theory on how the AP in the t-tubule is translated to Ca++ release in the SR?
DHPR (membrane protein complex on t-tubules) has voltage gated Ca++ channel
RyR releases Ca++ from SR
Depolarization -> conformational change in DHPR -> Ca++ release opens-> Ca++ out of SR
What can induce malignant hyperthermia?
Potent & Volatile anesthetics - halothane - succinylcholine => steady Ca++ leak activates Ca ATP pump - futile - heat producing - lethal
What are symptoms of malignant hyperthermia?
- rapid temperature rise -> >1/ 5 min
- muscle rigidity - masseter spasm
- Increase CO2 production
- Rhabidomyolysis (muscle breakdown)
- Hyperthermia
What drug can be used to reverse malignant hyperthermia?
Dantrolene -> block Ca++ release from SR
Why can skeletal muscles work, but not cardiac or vise versa?
Many genes code for same proteins
- isoforms
What terminates the myosin-actin interaction in muscle contraction?
Ca ATPase pump puts Ca++ back into SR -> cytoplasmic Ca returns to low level (<0.1micromolar)
Why is the t-tubule system necessary?
myofibrils are too large for the AP to diffuse through efficiently -> MUST have conduction system (50-100micrometers)
How is excitation-contraction coupling completed in cardiac muscle?
Ca must bind Ca-release channel - otherwise identical to skeletal muscle
How is excitation-contraction coupling completed in smooth muscle?
no need for t-tubules (1-2 micrometer diameter)
- do have some SR
How are tension and actin-myosin overlap related?
0 overlap = 0 tension
tension increases linearly with overlap
UNTIL
actin reaches central region of thick fillaments
-> 0 myosin head groups => plateaus
OR
if actin fillaments interdigitate in middle of sarcomere -> tension decreases
What is a motor unit?
muscle fibers innervated by a motor neuron
- each time neuron fires action potential - fibers innervated by neuron contract in unison
How many muscle fibers do each motor neuron innervate?
RANGE
3 in extra occular
10-20 in fine motor
100s in large muscles
total number of motor units in muscle = total number of muscle fibers
(each motor fiber innervated by ONLY ONE motor neuron)
How do motor units relate to the strength of contration?
more motor units -> more strength
How does the innervation of cardia and smooth muscle differ from the innervation of skeletal muscle?
innervated
BUT
innate excitability
- excitatory and inhibitory innervation modulate
linked by gap junctions (electrically coupled)
What are the types of muscle fibers?
slow
fast
intermediate
How do the muscle fiber types differ?
proportion of mitochondria
amount of oxidative enzymes
resistance to fatigue
speed of contraction
How many types of fibers are in a motor unit?
ONLY ONE
homogeneous
What 3 factors can grade tension in skeletal muscles?
- increased frequency of action potentials
- recruitment of additional motor units
- changing length of muscle (minor)
How is tension graded in cardiac and smooth muscle?
- neurotransmitters and hormone-like molecules
2. LENGTH - not fixed by attachements to bone
What are the stem cells for muscles? What is their function?
satellite cells
- source of new myoblasts to repair injury
How are satellite cells related to Duchene Muscular Dystrophy?
skeletal muscle cells weakened or damaged by absence of dystrophin
- satellite cells continuously repairing
=> depleted/ loose ability to keep up with degeneration
How does cardiac muscle repair itself?
0 satellite cells
- little or no repair after MI
How do smooth muscles repair themselves?
dedifferntiate -> divide -> regenerate/ redifferendiate!
- contribute to smooth muscle tumors?
- can occur anywhere!
When skeletal muscles get bigger, do the fibers grow, or are more fibers added?
already existent fibers grow
- have a set number of fibers
- grow or decline/ atrophy
What are the 4 major causes of muscle fatigue?
- ineffective propagation of AP in t-tubule (K build up, Na reduction)
- decreased or 0 release of Ca++ from SR
- decreased Ca++ affinity to troponin
- decreased force generated by myofilaments
What smooth muscles have action potentials?
longitudinal muscles of gut
uterus
bladder
(Ca++ not Na+ APs)
What are some of the cellular consequences of HCM?
interstitial fibrosis
dyplastic intramyocardial arterioles (disorganized sarcomeres-> ischemia - harder for aa to get blood there)
What are some phenotypes of HCM?
often asymptomatic!!!!
- some dyspena, angina, syncope
- cardiac murmur (LV outflow obstruction)
- Arythmias -> syncope/ sudden death
How is HCM diagnosed?
EKG, echo, genetic screeen
What is myostatin?
inhibitor of muscle growth
What are some current treatments of muscular dystrophy?
Symptomatic
- supportive
- leg braces
- surgical tendon release (rigidity- toe walking)
- CPAP
- Cortico steroids (side effects)
- Ambulatory assistance devices
- multidiciplinary care
Disease targeted
- Growth modulating agents (myostatin)
- Anti inflammatory - 2nd messenger modulators
- antisense oligonucliotieds (ASO) with EXON SKIPPING capacity ( skip incorrect stop codon)
- Supress stop codon
- Myoblasts/ stem cells
