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Skeletal Muscle
- contracts (shortens) quickly & its duration of contraction tends to be short-lived
- neuromuscular transmission is required for contraction (it will never contract if neurons are inactive)
- there is NO communication between individual skeletal muscle fibers
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Cardiac Muscle
- contracts quickly & does so for a long time → a single action potential results in continuous contraction
- contracts spontaneously: neuronal innervation isn't needed for a contraction to occur, it just modulates it
- gap junctions between myocytes allow for intercellular communication between the entire myocardium
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Smooth Muscle
- neuromuscular transmission (APs) can initiate contraction in some types but only modulates contraction in other types (may or may not need stimulation from a neuron in order to contract)
- its contractions are weak compared to those of skeletal/cardiac muscle & the muscle contracts very slowly
- gap junctions support intercellular communication between some types of smooth muscle myocytes but not others
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What are two different muscle fiber types?
- RED (slow twitch): many mitochondria & oxidative enzymes (AERobic); don't contract fast but CAN contract for long periods without fatiguing, eg. back muscles
- WHITE (fast twitch): bigger muscle cells, contract quickly; fewer mitochondria & oxidative enzymes (ANaerobic); quicker to fatigue, eg. quadraceps
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Slow Fibers (Type I, Red)
- are small in diameter, are innervated by smaller diameter motor axons → are less strong but have sustained contractions
- have fewer glycolytic enzymes
- a less extensive sarcoplasmic reticulum results in a SLOW release of Ca2+
- contain MANY mitochondria
- have a dense capillary network that contributes to a high O2 supply
- contain lots of myoglobin, an O2 binding
- protein that causes muscle to be Red
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Fast Fibers (Type II, White)
- are large in diameter, are innervated by larger diameter motor axons → have a lot of strength but fatigue quickly
- have a lot of glycolytic enzymes
- an extensive sarcoplasmic reticulum results in RAPID release of Ca2+
- contain FEW mitochondria
- have a limited blood supply & a low oxidative metabolism
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The Essential Difference Between Muscle Fiber Types
- white (Fast) are very good at producing STRONG contractions but b/c they don't derive their energy from aerobic metabolism (are anaerobic, contain few mitochondria) they FATIGUE more easily
- a forceful quick contraction = fast (white) twitch
- a sustained contraction = slow (red) twitch
- most muscles have a MIXTURE of red & white fiber types in them
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Multiunit Smooth Muscle
- each cell is innervated by 1 or more autonomic motor neurons
- action potentials are usually absent & contraction is triggered by neurotransmitters (NE or ACh)
- there is little to no electrical coupling between cells (can have tension in different parts of the organ)
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What does the electrical isolation of multiunit smooth muscle cells allow for?
FINER motor control results from no electrical coupling
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Unitary Smooth Muscle
- each myocyte doesn't have individual motor nerve innervation - there are gap junctions & extensive electrical coupling between cells so a contraction in one can spread to others (like cardiac muscle)
- myocytes usually spontaneously activate
- contraction is only modulated by neurotransmitters (NE or ACh)
- (unitary smooth muscle can contract without nerve stimulation)
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Skeletal Muscle Structure
- whole muscle
- ↓
- Fasiculus
- ↓
- Muscle Fiber (myocyte) = muscle cell
- ↓
- Myofibril: very long chains of sarcomeres
- ↓
- Sarcomeres: contractile units of the cell; made of thin & thick filaments
- ↓
- Myofilaments: actin & myosin

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- I band: light staining thin actin filament bisected by the Z line
- Z line: serves as an anchoring point for thin actin filaments (Z disk)
- Sarcomere exists from the dark Z line in one thin actin filament to the Z line in the next
- A band: dark staining THICK myosin filaments
- M line: line w/ proteins that reside in the middle of the A (thick myosin) band: hold the myosin together
- H band: slightly lighter area surrounding M line in the middle of the A (dark, myosin) band
- the bubbly/dotty stuff between myofibril striation = cell organelles (eg. mitochondria)
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The Sliding Filament Hypothesis
- muscle contraction is produced by actin & myosin filaments sliding past each other
- the Sarcomere overall shortens → a 'domino' effect of sorts that can cause the muscle to shorten by ~10% overall
- the Z-lines move CLOSER together
- neither the I nor A bands shorten (Z within the I band just moves)
- H band (surrounding M line) disappears - is filled in with thin filaments

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What does filament overlap & the length-tension relationship have to do with muscle contraction?
- when the muscle is too shortened/contracted OR overstretched only a low force can be generated (aka overly short or overly long sarcomere length)
- the best position for optimal force generation is when the sarcomere is at some intermediate length; this corresponds to where maximal TENSION can be generated

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Thin Filaments (I band)
- in skeletal muscle this consists of actin, tropomyosin, & troponin
- the filament itself is a double stranded helical polymer of actin molecules
- contains no cross-bridges
- has myosin-binding sites where myosin heads may bind
- F-actin is associated with 2 regulatory proteins: tropomyosin & troponin
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Tropomyosin
- 2 identical helices that coil around each other & sit in the groove between the 2 wound actin filaments
- active state: makes myosin-binding sites on actin accessible to myosin heads
- resting state: covers the binding sites; it interferes with the binding of myosin to actin when the muscle is relaxed

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Troponin
- controls tropomyosin by pulling it away from the myosin-binding site on actin filaments in the presence of Ca2+
- troponin T which binds to a single molecule of tropomysoin
- troponin C binds Ca2+
- troponin I binds to actin & inhibits contraction when bound ("I" for actin = I band & "Inhibits")
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What does the coordinated interaction of tropomyosin, troponin, & actin allow?
it allows for the binding of actin to myosin to be regulated by local changes in intracellular Ca2+
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What initiates a muscle contractions, or more specifically, the sliding filament hypothesis?
- an in increase in intracellular Ca2+ of course
- in all 3 types of muscle Ca2+ acts through regulatory proteins, not by direct interaction with the contractile proteins themselves
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Think Filaments (A band)
- bipolar assemblies of multiple myosin-II molecules, a double trimer made up of 2 intertwined heavy chains, two regulatory light chains, & two other “alkali” or “essential” light chains
- the heads of the heavy chains each can both bind to actin & have an enzymatic site for binding & hydrolyzing ATP
- the “alkali” light chain plays an role in stabilizing the head region
- the regulatory light chain regulates myosin ATPase activity & is itself regulated by Ca2+-dependent & Ca2+-independent kinases

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The Crossbridge Cycle
- responsible for generating the sliding movement of myosin along actin filaments that produces muscle contraction
- 0. Rest. ATP is bound to the myosin head & hydrolyzed but the energy of the reaction can't be released...
- 1. …UNITL the myosin head binds to actin
- 2. the release of the hydrolysis products is associated with the power stroke
- 3. the rotated & still-attached cross bridge is now in the rigor state
- 4. detachment occurs when a new ATP molecule binds to the myosin head
- 5. the ATP is hydrolyzed, activating the myosin head so it can rotate when [Ca2+] increases & bind to actin again

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What will terminate the crossbridge cycle?
- the cyclic reactions will continue as long as there is an ATP supply & the Ca2+ concentration (what's activating it) is maintained
- ATP binding to the myosin head allows the head to dissociate from actin & rotate back to the resting state
- the energy of ATP hydrolysis is stored in the unbound “resting” myosin head
- Ca2+ promotes binding of the myosin head to actin; this releases the stored energy causing the cross bridge to rotate, forcing the filaments to slide over one another
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How is regulation of crossbridge cycling different in smooth muscle?
- Ca2+ binds to calmodulin (a protein similar to troponin C), causing it to activate myosin light chain kinase (MLCK)
- the activated MLCK phosphorylates the regulatory light chain of myosin, increasing its ATPase activity, allowing myosin to bind to actin & initiate contraction
- the energy for crossbridge cycling is NOT stored in the myosin head, but must be generated by ATP hydrolysis before contraction can begin
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Excitation–Contraction (EC) Coupling
the processes by which excitation (electrical activity at the cell surface) leads to an increase in the concentration of intracellular Ca2+
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How is the Ca2+ concentration raised in muscle fibers so contraction occurs?
- muscle fibers are larger in diameter than the post-synaptic structure in synapses, therefore having voltage dependent Ca2+ channels only on the surface of a myocyte membrane ISN'T going to do much
- T (transverse) tubules solve this problem: are indentations of plasma membrane ~ every 2 sarcomeres that invaginate DEEP into the muscle fiber
- have voltage dependent gates expressed on T tubule surface → gets Ca2+ signal into the depths of the muscle
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What is the second way a nerve signal is propagated through a muscle?
- through the release of Ca2+ from the sarcoplasmic reticulum - cisterns of smooth ER (membrane bound compartments) full of Ca2+ surrounding T tubules
- voltage dependent Ca2+ channels in T tubules trigger the release of Ca2+ from big stores in the sarcoplasmic reticulum
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Initial process of Skeletal Muscle Contraction
- 1. action potentials are propagated from the NMJ along the skeletal muscle membrane & down T-tubules
- 2. when the triad region of the T-tubules is depolarized, L-type Ca2+ channels (clustered in groups of four in the T-tubule membrane) are activated
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DHP receptors
- L-type voltage-gated Ca2+ channels found on the T-tubule membrane
- function as the voltage sensor in EC coupling
- each of the four voltage-gated Ca2+ channels are called DHP receptor b/c they're inhibited by dihydropyridines
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Depolarization of the T-tubule membrane brings about conformational changes in each of the four L-type Ca2+ channels resulting in:
- 1. Ca2+ enters the cytosol through the 4 channel pores
- 2. a conformational change occurs in Ca2+-release channels located in the SR membrane→ SR Ca2+ release
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Ryanodine Receptors
- voltage-gated Ca2+ channels found on the sarcoplasmic reticulum membrane
- *the interaction between the T-tuble L-type Ca2+ channels & the closely associated SR Ca2+-release channels is the BASES for SR Ca2+ release
- are inhibited by a class of alkaloids including ryanodine, a plant alkaloid
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What initiates Ca2+-induced Ca2+ release (CICR) from the SR?
- passage of small amounts of Ca2+ through the T-tubule L-type Ca2+ channels
- this mechanism is not absolutely necessary for EC coupling in skeletal muscle but IS a requirement in cardiac muscle
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Malignant Hyperthermia
- caused by mutations in SR ryanodine receptors
- this mutation causes no observable phenotype under normal conditions, however gaseous anesthetics (halothane) cause the mutant receptor to become more sensitive to cytosolic Ca2+
- normal Ca2+ release during a muscle contraction triggers massive & uncontrolled release of Ca2+ from the SR
- this causes muscle rigidity & a dramatic increase in muscle metabolic activity due to a large increase in ATP consumption in an attempt to return Ca2+ back into the SR via a usual ATP pump
- this causes increased oxygen consumption & elevated body temperature (hyperthermia) which can cause circulatory collapse & death if not treated
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How is malignant hyperthermia treated?
with dantrolene, a muscle relaxant, which lowers the Ca2+ affinity of the ryanodine receptor & blocks the uncontrolled release of calcium from the SR
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