Download Lectures 4-6: General Principles of Skeletal, Cardiac, and Smooth

Lectures 4-6: General Principles of Skeletal, Cardiac, and Smooth Muscles I and II
Three Types of Muscle Tissue: (all muscle is specialized in movement)
 Skeletal
 Cardiac
 Smooth
Skeletal Muscle:
 Attached to bone and moves parts of the body
 Rapid movements
 VISIBLE motion and VOLUNTARY control
 Organized into DISCRETE organs: skeletal muscles
Cardiac Muscle:
 Muscle of the heart
 Beating automatically in a rhythmic and coordinated fasion
 NOT under voluntary control
 Organized into DISCRETE organs: the heart
Smooth Muscle:
 Walls of hollow visceral organs
 Controls passage of substances (can be rapid but usually is not)
 NOT under voluntary control
 Incorporated into EXISTING organs
Fasciae of Individual Muscles:
 Individual muscle invested in epimysium
 Fascicles invested in perimysium
 Each muscle fiber in a fascicle is invested in endomysium
Types of Fascia:
 Superficial fascia- loose connective tissue with variable fat amounts just deep to the skin
 Deep Fascia- dense connective tissue just deep to superficial fascia- wrapping for most of the body
The Muscle Fiber:
 Multinucleated, striated, very large
 100 micrometers thick and 30 cm long: hence the name muscle fiber
 Striation is due to protein arrangements within the cell
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Multi-nucleation is because skeletal muscle cells are syncitia of myoblasts.
Sarcolemma- plasma membrane
Sarcoplasm- cytoplasm
o Contains organelles like nuclei and mitochondria
o Myofibrils (contractile units) make up 80% of the volume
Myofibril:
 Made up of bundles of myofilament proteins: actin and myosin
o Thin filaments:
 Actin:
 Globular G-actin polymerizes into 2 alpha helical strands: F-actin
 Actin has myosin binding sites
 Tropomyosin:
 Covers the myosin binding sites at rest to prevent interaction of actin and myosin
 Align head to tail (one tropomyosin spans 7 G-actins)
 Troponin
 Complex of three globular proteins located along tropomyosin
o Troponin T: attaches the troponin complex to tropomyosin
o Troponin I: inhibits actin and myosin from interacting (like tropomyosin)
o Troponin C: binds calcium to initiate muscle contration
 Nebulin- “molecular ruler”- determines length of filament
o Thick filaments:
 Assembly of myosin proteins
 Each myosin consists of two trimers coiled around each other
 Each trimer: one heavy chain and two light chains
 Head region of heavy chain binds ATP and actin
Organization of Myofilaments:
 Arranged to give skeletal and cardiac myocytes a striated appearance
 Sarcomere- repeating segment of myofibrils extending longitudinally between Z disks
 Z-diskso dense disk shaped structures with the diameter of the myofibril
o Provide anchorage and spacing for thin filaments
o Contains filamentous proteins:
 Titin- anchors THICK filaments to Z-disks and important for elastic qualities of muscle
 Alpha-actinin- binds thin filaments to Z-disk
o When several adjacent myofibrils are viewed, Z-disks line up to form Z-line
 A- bands- dark and created by thick filament presence
 I-bands- light and created by thick filament absence and presence of thin filaments
 H-zones- Part of A band that is only thick filaments. Thin filaments do not reach. Appears lighter
 M-line- Dark center of the H-zone made up of protein strands holding thick filaments together
Dystrophin:
 Large protein that helps anchor the entire contractile array to the cytoskeleton and sarcolemma
 Causes force to be distributed to the various layers of fascia
 Clinical significance: Muscular Dystrophy – degeneration of muscle and replacement with fat and fibrous
tissue
o Duchenne Muscular Dystrophy:
 mutation in Dystrophin gene which eventually affects respiratory muscles and patients don’t
make it past age 30
 Sarcomere moves independently of the sarcolemma and causes membrane tears
 The tears allow calcium influx which activates proteases that digest the contractile proteins
The Muscle Fiber:
 Sarcoplasmic reticulum:
o in all three muscle types
o type of smooth ER surrounding each myofibril
o periodically has dilated sacs : Terminal cisternae
o Terminal cisternae run in pairs at the A-band/I-band junctions
 T-Tubules:
o skeletal and cardiac muscle
o invaginations of the sarcolemma, sandwiched between pairs of terminal cisternae of the Sarcoplasmic
reticulum : called Triad
 Caveolus: equivalent of T-tubules found in smooth muscle
Excitation-Contraction Coupling:
 Transduction of an electrical signal into a muscle contraction triggered by rise in intracellular calcium (in all 3
muscle types)
 Rise in calcium comes from:
o Action potentials (in all 3 muscle types)
o Hormones (cardiac and smooth muscle)
 Steps:
o Action potential crosses the synapse of the neuromuscular junction
o It propagates along the sarcolemma and reaches the interior of the cell at the T-Tubule
o Causes depolarization of the triad region
o This induces opening of the voltage gated L-type Calcium channels (aka dihydropyridine receptors)
 Allows Ca to enter through the receptors (this Ca is not necessary for contraction)
 L-type receptos mechanically activate ryanodine receptors to release Ca into intracellular fluid
o When Ca concentration rises, it binds to troponin-C, pulling tropomyosin away so that myosin binding
sites are uncovered.
 Muscle Contraction:
o Each stroke is jerky
o All together- smooth contraction
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Contraction duration depends on:
o Presence of action potentials
o Availability of ATP:
 High energy phosphate bonds stored as creatine phosphate
 Creatine kinase cleaves Pi when energy is needed to make ATP from ADP
 Supplies 10 seconds worth of ATP. Glycolysis kicks in after that
o Presence of free calcium
o Contraction is called “sliding filament model” Myosin heads pull the thin filaments towards the center of the sarcomere so that they slide
past thick filaments
 Causes the sarcomere to shorten
Changes in sarcomere when Muscle Contracts:
 Distance between Z-disks decreases
 I-bands shorten
 H-zones disappear
 A-bands do not change (thick filaments don’t change in length)
Muscle Relaxation:
 When Calcium is removed from the cytosol by
o A Calcium pump
o A sodium-calcium exchanger
 When levels drop, troponin C is no longer bound by Calcium and tropomyosin can bind and block the actin
sites to prevent cross bridges from forming.
 Sarcomeres return to original length by:
o Elastic forces : titin and nebulin
o Opposing muscle contractions
o Gravity
Types of Contraction:
 Isometric contraction: muscle develops tension WITHOUT changing length
 Isotonic contraction: develops tension WITH length change (shortening or lengthening)
 Twitch- cycle of contraction and relaxation due to one action potential. Generates tension
 Tension:
o Total force generated by muscle
o Sum of all the forces generated by all the independently cycling actin-myosin cross bridges
o Measured by Dynamometer
o Force of a single cross bridge- 5 pN
Strength of Muscle Contraction:
 Can be changed by:
o Changing stimulus frequency”
 A single twitch lasts 25-200 ms
 The action potential lasts a few milliseconds
 A second action potential that is generated before the original one subsides stimulates a
TWITCH
 The twitch is superimposed on the residual tension of the first twitch- SUMMATION
 Tetanus:
 When the stimulation frequency is increased to the point where the individual twitches
are so close that they fuse
 This happens because:
o When the action potentials are in rapid succession, the SR does not have time to
resequester calcium
o This causes calcium concentration in the sarcoplasm to rise
o As the Ca concentration rises, the strength of the contraction increases
Proposed Mechanism:
 Tropomyosin has 4 calcium binding sites: first two with a lower affinity than the second two
 As Ca rises, more Ca is bound and more tropomyosin is moved to uncover myosin binding sites
 Shifting one tropomyosin may cause the next tropomyosin to shift
 During tetanus, additional twitches create heat
 Heat helps the myosin ATPase function better
 The FORCE of the contraction is primarily controlled by fiber recruitment
o Changing stimulus intensity:
 Motor unit- one motor neuron and all the muscle fibers it supplies by its axon processes
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Fine control muscles have few muscle fibers per motor unit
Muscles involved in strength and gross movements: may have 200 muscle fibers per motor unit
Twitch Velocity:
 Fast twitch fibers
 Slow twitch fibers
 Ration of fast to slow twitch fibers in muscle depends on function
o If predominantly fast twitch, peak tension may be reached very quickly (eye
muscles)
 To recruit additional fibers, activate more motor units
o Size Principle of Recruitment:
 If a muscle is subject to high tension, small motor units (slow twitch fibers) are recruited first
 THEN if tension needs to be increased, larger motor units (fast twitch) are recruited
o Length-tension Relationship:
 Forms of tension:
 Passive tension : tension by stretching a muscle to different lengths
 Total Tension: stimulating a muscle to contract at different lengths
 Active tension: Total tension – passive tension = active tension
 Mechanism:
 At optimal length, there is maximum overlap between thick and thin filaments- max
tension
 At greater or less than optimal length, NO maximum overlap, less than max tension
 Pre-load:
 Amount of tension in muscle right before contraction
o Skeletal muscle: pre-load optimized at resting length
o Cardiac muscle- preload optimized when heart is stretched prior to contraction
o Muscle tone- state of partial contraction where sarcomere length is optimized
o Tension-Velocity Relationship:
 Afterload- amount of tension a muscle must generate to overcome physical resistance
 The greater the afterload, the less the velocity of contraction (slower cross bridge cycles)
Practical aspect:
 Physical principles in addition to muscle physiology govern the amount of afterload a muscle can overcome
 Arm curl- develop max tension shortly after exercise starts but for PHYSICAL reasons, amount of weight we
can move increases if exercise is started near the end point
CARDIAC MUSCLE:
 Skeletal and cardiac muscle- similar in need to produce rapid strong contractions. Different in nature of
contraction.
 Cardiac cells do NOT extend the length of the heart- short and connected by intercalated discs
 Intercalated discs- how all cardiac muscle cells are ultimately connected to each other- SINGLE UNIT
 Cardiac cells exhibit extensive branching (not linear like skeletal muscles)
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Similar to skeletal muscle:
o Contractile machinery organized into sarcomere with same proteins
o Striated
o Has a sarcoplasmic reticulum but it is LESS DENSE and LESS DEVELOPED than skeletal
o Also contains T-tubules which also contain LESS DEVELOPED connections to the SR than skeletal
Excitation-Contraction coupling:
o Unlike skeletal, absolutely requires extracellular calcium to contract (skeletal uses both intra and extra)
o Unlike skeletal- no interaction between L-type Ca channels of T-tubule and ryanodine receptors
 Ryanodine receptors are Ca gated Ca channels in cardiac muscle:
 Requires binding of extracellular calcium that came in from the T-tubule so that the
receptor on the SR can release its calcium into the cell
 Recall: in skeletal muscle, you can have a muscular contraction with calcium that is only
coming from the sarcoplasmic reticulum because there was a PHYSICAL connection with
the ryanodine receptor that allowed calcium out.
Contraction:
 Cardiac muscle contraction different from skeletal in 2 ways:
o All heart muscle cells contract in unison
o Different action potential
 Action potential spreads very rapidly because intercalated discs feature gap junctions allowing
quick passage of ions. (all cells depolarize nearly together)
 Much longer absolute refractory period because L type Ca channels of cardiac myocytes create
SLOW inward calcium current
 This long absolute refractory period is GOOD because it prevents twitches from
summation thereby preventing tetanus which would be lethal in the heart
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The long absolute refractory period also allows sustained contractions(last longer)
o Allows time for ventricles to empty of blood completely
Control:
 Skeletal is under voluntary control, cardiac is under involuntary.
o Heart has autorhythmicity (beat on its own) due to intrinsic cardiac conduction system
o Cardiac muscle controlled by autonomic nervous system (sympathetic and parasympathetic)
Contractility:
 Skeletal muscle:
o Increase contraction strength by bringing motor units or inducing tetany
o Can’t do any of this in cardiac.
o Increase contraction strength in cardiac by increasing intracellular calcium HORMONALLY
 norepinephrine: as neurotransmitter released at nerve terminal
 Epinephrine: as hormone secreted by medulla
o BOTH epi and norepi bind to beta adrenergic receptors, activated cAMP 2nd messenger system,
activate PKA which phosphorylates:
 L-type Ca channels:
 Opens them, increase Ca influx (quicker relaxation and quicker contraction)
 SERCA pump:
 Phospholamban activation allows SERCA pump to cycle faster ( INCREASED HEART RATE)
Damage:
 No satellite cells in cardiac muscles so repair occurs by FIBROSIS
 Fibrosis decreases the ability of the heart to stretch and contract properly
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SMOOTH MUSCLE:
 Located in walls of hollow organs, eyes, skin (associated with hair)
 Tasks on less urgent time scale than cardiac/skeletal muscle: contracts for a longer time and uses less energy
 Smooth (and skeletal) muscle fibers are arranged LINEARLY and CIRCULARLY
o Linear:
 usually for skeletal but found in longitudinal smooth muscle of GIT (propels bolus of food)
 arrector pili muscles pull on hairs and elevate them (good bumps)
o Circular: (can also be seen in skeletal)
 Contraction constricts a pathway, relaxation dilates it.
 Usually smooth muscle but can be skeletal
 Gut- movement of food boli
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 Iris- regulation of amount of light passing
Microanatomy of smooth muscle:
o Bundles or sheets of elongated fusiform cells, NOT striated
o Single centrally located nucleus
Smooth Muscle Fiber:
o Actin and myosin organized into thick and thick filaments but are side-polar NOT bipolar (skeletal)
o NO sarcomeres, NO striations, NO Z-discs
o Alpha-actinin acts as a Z-disc
o They have a sarcoplasmic reticulum but no T-tubules: CAVEOLUS instead (rich in Ca channels)
o Thin filaments:
o Actin
o Tropomyosin
o Caldesmon and Calponin (instead of troponin)
Excitation Contraction Coupling:
o Unlike skeletal muscle, source of Calcium comes from action potentials AND hormone signaling
o They don’t form neuromuscular junctions. They form varicosities with neurotransmitters
Two ways to get calcium spike:
o Voltage gated calcium channels in the caveoli
o Activation of G protein complex which leads to opening of calcium channel on SR, allowing calcium in
Myosin ATPase:
o In striated muscle, myosin ATPase is constitutive active and the only thing limiting it is how fast troponin can
move tropomyosin out of the way and uncover the binding sites for actin on myosin
o In smooth muscle, myosin ATPase is NOT constitutively active. It needs to be turned on:
o Calcium binds calmodulin
o Calmodulin binds to myosin light chain kinase and activates it
o Myosin light chain kinase phosphorylates the regulatory light chain of myosin to ACTIVATE it
o Now myosin can hydrolyze ATP with its ATPase activity in order to pull on actin
o Overall: need an ATP to activate it and an additional ATP for each pull
Caldesmon and Calponin (part of thin filaments)
o At low calcium, caldesmon and calponin inhibit myosin ATPase activity
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Characteristics of Smooth Muscle Contraction:
o Speed:
 10x less frequent cross-bridge cycling than striated muscle (but stronger force)
o Powerstroke:
 Side-polar arrangement permits greater shortening of contractile unit (otherwise similar steps to
striated)
o Termination:
 The only way to turn off Myosin is by removing the phosphate that activated it: myosin
phosphatase
 decrease in calcium does not turn it off
Types of Smooth Muscle:
o Phasic:
 Contracts in waves (peristalsis in intestines)
 Autorhythmic (like cardiac muscle)
 Contraction in unison (like cardiac muscle)
 Aka single-unit smooth muscle:
 Electric coupling of cells by gap junctions: this propagates a single action potential: contract
in unison
 GIT, bladder, uterus: necessary to contract as a unit
o Tonic :
 Steady contractions (sphincter muscle) and only periodic relaxation.
 Summation is possible (like skeletal)
 Contractions are controlled (like skeletal)
 Aka multi-unit smooth muscle:
 Innervation of a few cells by a single neuron, very little electric coupling
 Each cell behaves independently
 Iris and lens: require this because they require a high degree of control.
Predominance:
 Usually both phasic and tonic present but one type predominates
Latch state:
 Latch state allows tonic smooth muscle to contract for a long time while using 300x less ATP than skeletal
 When Ca concentration drops, it does so less drastically in tonic muscle than in phasic:
o Myosin phosphorylation occurs but DEphosphorylation predominates
Regeneration:
 Hyperplasia and Hypertrophy (unlike skeletal and cardiac)
 Grows well by addition of new myocytes and regenerates well due to mitotic abilities
Contractility:
 Even if they stretch (bladder), then maintain contractility by length adaptation
 They do this by shifting left and right to maintain maximum tension at non-optimal lengths.
o They can replicate and add units while stretched and remove those units when back to normal length
o