Physiology Review Sheet - University of Michigan



Physiology Review Sheet

Striated Muscle Structure/Function, Muscle Performance, Muscle Protein Structure and Energetics, Smooth Muscle, Clinical Examples of Deranged Intramuscular Ca2+ Homeostasis

• 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

o isotonic: constant load on muscle

o 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

o [pic][pic]

o force of contraction depends on length of sarcomere prior to contraction

o optimum length = max force

o 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

o [pic]

o preload: initial length of muscle; stretch; determines max force possible

o afterload: additional load without changing muscle length; determines velocity

o hyperbolic relationship – velocity decreases rapidly with increased afterload

o power = F * V

o max power occurs at 1/3 max isometric force in skeletal muscle

o 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

o 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

• 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)

• 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

o 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)

o 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

• 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

▪ glucose metabolism = PFK deficiency – very similar

▪ both:

• muscle pain/ contractures

• muscle destruction can result

o Pathophysiology

▪ high intensity activity brings it on (anaerobic)

▪ aerobic activity is not a problem

o 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

o Ischemic Exercise Test

▪ test of serum lactate pre and post exercise

▪ test for these diseases

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Total force

Active force

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