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 Ca 2+
influx induces release of Ca2+ from SR via RyR

Total force

Length-Tension Relationship
Active force

force of contraction depends on length of sarcomere prior to contraction

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
o

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

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
o
o

at long lengths, less overlap between thick and thin filaments cant generate as much force
at length = thick filament + 2 thin filaments (3.6 m) 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]

2+
o
Ca 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 wont 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 O 2 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 (McCardles 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