Download Physiology Review Sheet

Physiology Review Sheet
Striated Muscle Structure/Function, Muscle Performance, Muscle Protein Structure
and Energetics, Smooth Muscle, Clinical Examples of Deranged Intramuscular Ca2+
Homeostasis
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Skeletal Muscle Structure [Note: not sure which parts you need to know for Micro and which for Phys]
o myofibril (grouped into muscle fiber (multinucleated individual cell) which are grouped into muscle
fascicles)
 sarcomeres (space between 2 Z bands)
 Z-band
o thin filaments insert into this
 I band
o light band (1/2 on each side of Z)
o actin
o length varies due to filaments sliding
 A band
o dark band
o myosin, actin
o fixed length = length of thick filament
 H zone
o light zone in center of A band
o myosin
 M line
o dark line in center of H zone
o myomesin (M protein)
o connects thick filaments
o myofilaments
 thin filament – actin
 G-actin (globular)
 F-actin (filamentous)
o 2 strands of F-actin forming a double helix (string of pearls) in muscle
 Tropomyosin
o lies along actin groove
o covers myosin binding sites during low Ca2+ levels
 Troponin
o TnT – binds tropomyosin
o TnC – binds Ca2+ and relieves inhibition of Tm
o TnI – inhibits actin-myosin interaction at low Ca2+
 thick filament – myosin
 single heavy chain and 2 light chains
 heavy chains
o tail
o role in filament assembly
 globular heads
o S1 = head region
 ATPase activity
 actin binding site
o S2 = hinge
 opposite polarity at center leaves central bare zone – no heads
o reason for plateau in force-length curve
Motor unit = a motor neuron and all the muscle fibers (cells) it innervates
Mechanics
o isometric: no change in total muscle length
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isotonic: constant load on muscle
stimulation frequency
 sg stim = twitch = one nerve fires once and that motor unit contracts once
 second AP before relaxation is complete begins wave summation – new contraction occurs at
greater force than previous one (temporal summation)
 treppe – high frequency of stimulation generates multiple contractions before any relaxation is
complete resulting in a staircase appearance in force/time curve
 tetanus – treppe summates to smooth even contraction; note: if too high a frequency or for too
long, force will decline
Excitation-Contraction Coupling
o more skeletal muscle structure
 sarcolemma
 aka plasma membrane of muscle cell
 electrically excitable; propagates APs like a nerve
 T tubules
 invaginations of sarcolemma (still excitable)
 open to ECF
 at A-I junction for fast skeletal muscle (at Z bands for others)
 sarcoplasmic reticulum
 stores and releases Ca2+
 lots of Ca2+ pumps (Ca-ATPase) to sequester it in SR in longitudinal regions
o phospholamban
 SR protein assoc with Ca-ATPase in slow skeletal, cardiac, and smooth
muscle
 inhibits Ca-ATPase
 inhibited by phosphorylation (so pump can work)
 useful to increase cardiac contractility with certain drugs
 terminal cisternae
o widened regions near junction with T tubules
o Ca2+ stored here bound to calsequestrin
o immediately next to T tubule = junctional SR
 triad
 T tubule flanked by SR on both sides
 ryanodine receptor (RyR)
o foot proteins in terminal cisternae separating T tubule and SR membranes
o Ca2+ release channel
 dihydropyridine receptor (DHPR)
o voltage-gated Ca2+ channel (VGCC)
o tons in T tubule adjacent to terminal cisternae
o Contraction sequence of events (overview)
 motor neuron fires and elicits AP on sarcolemma
 AP propagates along sarcolemma and into T tubules
 signal causes conformational change in DHPR of T tubule to open the RyR of the SR  releases
Ca2+
 Ca2+ binds troponin C
 actin and myosin interact, slide past each other, generate force
 Ca-ATPase in SR takes up excess Ca2+ inside cell and ends contraction
 Note: in cardiac muscle, EC [Ca2+] matters – DHPR is a Ca2+ channel in cardiac muscle and Ca2+
influx induces release of Ca2+ from SR via RyR
Length-Tension Relationship
Total force
Active force
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force of contraction depends on length of sarcomere prior to contraction
optimum length = max force
total force – passive force = active force
 active force stimulated by contraction
 Note: active force declines at long and short lengths, but passive force continues to increase
with length until muscle tears
Force-Velocity Relationship
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preload: initial length of muscle; stretch; determines max force possible
afterload: additional load without changing muscle length; determines velocity
hyperbolic relationship – velocity decreases rapidly with increased afterload
power = F * V
max power occurs at 1/3 max isometric force in skeletal muscle
shorter muscles contract slower
 not very important in muscle because limited ROM due to skeleton
 very important in heart where muscle has a large length range
Assembly of sarcomeres
o in parallel = ↑ force
o series = ↑ velocity, shortening capacity, and tension cost (ATPase)
Factors influencing total force developed
o [Ca2+]I -- # of activated actin filaments
o # of crossbridges overlapped
o # of crossbridges able to interact limited by speed
o spatial summation
 due to motor unit firing (not all cells of unit are in same place; they are of same time)
 depends on:
 twitch duration of fibers (depends on myosin ATPase)
 frequency of firing
 # of motor units recruited
 size of motor units (# of fibers and fiber cross-section)
o recruitment
 increase # of motor units firing
 small to large
 @ highest forces . . . increase force by increasing firing rate
Sliding Filament Model of Contraction
o tension of muscle fiber is proportional to extent of thick and thin filament overlap
o insert graph B p10
 at long lengths, less overlap between thick and thin filaments – can’t generate as much force
 at length = thick filament + 2 thin filaments (3.6 μm) – no overlap – no force
 at short lengths (?) – double filament overlap causes less ability to generate force
ATP hydrolysis by mysoin releases heat – also dependent on degree of overlap between thick and thin
filament
o Thin filament regulation
 inhibition of actin-myosin interaction regulated by tropomyosin and troponin
 regulated by Ca2+ binding of TnC → conformational change to TnT and TnI → moves Tm off
actin binding site on myosin
 [smooth muscle is regulated by thick filament]
o Ca2+ sensitivity:
 sensitizers change Ca2+ binding affinity of TnC so that lower Ca2+ would affect more TnC and
activate more actin
 phosphorylation of regulatory proteins alter Ca2+ signal transduction
 different isoforms of Tn and Tm modulate sensitivity
o Crossbridge Cycle (occurs many times during contraction)
 myosin bound to ATP won’t bind actin
 myosin hydrolyzes ATP to ADP and Pi and binds actin (use 1 ATP / cycle)
 releases ADP and Pi (enhanced by actin binding) and undergoes power stroke (still linked
to actin = rigor link)
 binds fresh ATP and dissociates from actin
Muscle Metabolism
o Fenn effect: isotonic contraction releases more energy than isometric contraction – feedback between
mechanical constraints and rate of crossbridge cycling
o Sources of ATP for contraction
 muscle stores of ATP
 low amounts
 immediately available
 creatine phosphate
 3-5x as much as ATP
 very rapid
 Lohman Reaction
o ATP  ADP + Pi . . . . . . + . . . . . . PCr + ADP  Cr + ATP (one step
production of ATP)
 glycogen
 large stores
 can be metabolized by glycolysis (rapid, limited, lots of ATP, but relatively inefficient;
make lactic acid) or by oxidative phosphorylation (slower, limited, huge amounts of
ATP, efficient)
 exogenous stores (depends on diet)
 uses oxidative phosphorylation to generate lots and lots of ATP efficiently, but slowly
 Feedback mechanisms involve
 ADP & Pi
 Ca2+
o activate phosphorylase cascade to produce glucose from glycogen
o increase permeability of sarcolemma to glucose
 increased blood flow
o improve O2 flow
o remove lactic acid
o Recovery of oxygen consumption (oxygen debt)
 spring or burst of activity
 must resynthesize high energy phosphates used from PCr
 ultimately, nearly all ATP used in contraction is resynthesized during ox-phos
Diversity of Proteins
o Skeletal muscle contractile and regulatory proteins are NOT all the same – isoforms (myosin, actin, Tm,
Tn)
o Myosin isoforms (be familiar with varying characteristics)
 fast glycolytic (FG)
 white
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 type IIb
 high levels of fast ATPase
 few mitochondria
 dense SR
 large fiber diameter
 low oxidative enzyme activity
 low mitochondrial ATPase
 high glycolytic activity
 low myoglobin
 slow oxidative (SO)
 red
 type I
 low levels of slow ATPase
 intermediate # mitochondria
 intermediate SR
 intermediate fiber diameter
 high/intermediate oxidative enzyme activity
 intermediate mitochondrial ATPase
 low/intermediate glycolytic activity
 high myoglobin
 fast oxidative glycolytic (FOG)
 red
 type IIa
 high levels of fast ATPase
 lots of mitochondria
 dense SR
 small fiber diameter
 intermediate/high oxidative enzyme activity
 high mitochondrial ATPase
 intermediate/low glycolytic activity
 high myoglobin
Cardiac Muscle
o structure
 striated, sarcomeres
 similar to SO skeletal muscle
 sarcolemma with T tubules
 DHP receptor is a voltage sensor AND a Ca2+ channel – Ca2+ induced Ca2+ release
(CICR) – not voltage gated as in skeletal
 Na+- Ca2+ exchanger
o forward: Ca2+i exits, Na+e enters
o reverse: Ca2+e enters (mechanism of ouabain and digitalis → inhibits Na+ pump
→increases [Na+]i reverses pump and increases Ca2+i
 lots of mitochondria and lower PCr
o function
 myocytes electrically coupled
 no recruitment. . . vary [Ca2+]i to regulate force
 mechanism for force generation the same for skeletal muscle
 less myofilaments in parallel – less force/unit cross sectional area
 energy cost is less → slower cross bridge cycling rate
Smooth muscle
o structure
 spindle-shaped cells
 proteins
 actin/myosin in scattered arrangement (no sarcomeres)
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fewer myosin filaments per actin
dense bodies containing -actinin anchor actin
intermediate filaments connect dense bodies to cytoskeleton
poorly developed SR – can store Ca2+
no troponin
energetics
 sustains contraction longer without fatigue & lower O2 consumption
 latch state: maintain force with reduced crossbridge cycling velocity
 force-length similar to skeletal
 oxidative contraction
 low energy requirements (supply=demand)
 low PCr pool (not needed)
 no oxygen debt
 glycolysis for membrane function
 lactate is produced under fully oxygenated conditions
 fuels membrane pumps (ATPases)
 metabolic compartmentation (have anaerobic and aerobic going on at same time)
Smooth Muscle Excitation-Contraction Coupling
 General
 many types of Ca2+ channels and membrane receptors
 no fast Na+ channels
 AP carried via Ca2+ channels, and Ca2+ acts as second messenger
 automaticity
o pacemaker potentials
o slow waves (APs occur in bursts)
 oscillations in Nai-Ko pump
 act as stretch receptors (in GI tract, bladder, uterus, some blood vessels)
 neurotransmitters can activate
 mechanism of [Ca2+] I elevation → contraction
 Ca2+ entry via voltage-dependant channels and receptor operated channels
 Ca2+ release from SR via Ca2+ or IP3
o consequence of Ca2+ channels opening in PM
o G-protein cascade with DAG or IP3 directly open Ca2+ in SR
 angiotensin II acts via G-protein activated phospholipase
 DAG and phosphorylation of PK-C activates slow Ca2+ channels
– triggers release from SR
 IP3 acts as 2nd messenger activating SR Ca2+ channels
 reversed Na+/ Ca2+ exchange (follows gradient)
 inhibition of SERCA (SR Ca2+ reuptake pumps)
 mechanism of smooth muscle relaxation (lowering [Ca2+]i) – favored by high [Ca2+]i
 SERCA
 Na+/ Ca2+ exchanger in forward direction
 sarcolemma Ca2+ ATPase channels
 inhibition of sarcolemma Ca2+ channels
 transduction of Ca2+ signal at level of contractile filaments
 activation
o Ca2+ binds calmodulin (free in cytosol)
o Ca2+/calmodulin activates MLCK
 phosphorylates MLC 20
 activates ATPase and allows crossbridge formation
 sliding filament
 relaxation
o MLCP (phosphatase) (may regulate latch state)
o dephosphporylates MLC 20
 modulation of Ca2+ sensitivity
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 Ca2+ entry blockers
 inhibit binding of Ca2+ /calmodulin to MLCK → less MLC phosphorylation
 stimulation of MLCP
Malignant Hyperthermia
o clinical features
 potentially fatal
 triggered by anesthetics (ether, or any of the –thanes) or muscle relaxants (succinyl choline)
 hyperthermia and muscle rigidity
 family history
 priming factors: stress, youth, prolonged surgery
o Muscle Disorder
 a mild reaction increases creatine kinase
 survivors of severe reactions have rhambdomyolysis (severe destruction of muscle)
 abnormal sensitivity to halothane or caffeine
o Porcine Stress Syndrome
 stress induced MH in pigs
 provides excellent clinical model (pathophysiology, treatment, molecular bio)
o Molecular biology
 defect in RyR (triggers open and keep open)
 increase in Ca2+ ATPase activity (trying to pump Ca2+ back into SR)
 increase in myosin ATPase activity
 muscle metabolism increases to try to meet ATP demands
 depletion of ATP leads to cell death
o Reaction
 early
 increase venous CO2, lactate, and temperature (anaerobic metabolism increasing)
 decreased venous O2 (increasing aerobic metab)
 increasing body temp
 indicates hypermetabolic state, but only Ca2+ reuptake channels working overtime
because no muscle rigidity yet
 mid
 increasing body temp (even to baseline)
 muscle rigidity
 increased serum K+, Ca2+, catecholamines
 stressed systemic response
 late
 temp up to 43 C (109.4 F)
 lethal [K+], [Ca2+]
 muscle membrane failure
 CO2 tension above 100 mm
o Dantrolene Sodium
 binds RyR (pH 6.5-7.5)
 inhibits Ca2+ release from SR, but does not shut off completely
 highly selective for muscle
 administered intravenously
 highly lipophilic (goes everywhere)
 reverses ongoing reaction and blocks future one
 wears off after ~ 12h
Myophosphorylase Deficiency (McCardle’s Disease)
o Clinical Features
 hereditary
 cramping, weakness, contractures (without AP) during high intensity activity
o Impaired Muscle Glucose Metabolism
 glycogen metabolism problem =myophosphorylase deficiency – cannot go from glycogen to
lactate
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glucose metabolism = PFK deficiency – very similar
both:
 muscle pain/ contractures
 muscle destruction can result
Pathophysiology
 high intensity activity brings it on (anaerobic)
 aerobic activity is not a problem
Problems of muscle ATP deficiency
 increased [Ca2+] – cannot pump back into SR
 myosin ATPase is uncontrolled (leave in rigor state)
 membrane integrity is lost
 leads to all other problems
Ischemic Exercise Test
 test of serum lactate pre and post exercise
 test for these diseases