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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