Chapter

Muscles and Muscle Tissue

Muscle Overview

• The three types of muscle tissue are skeletal, cardiac, and smooth

• These types differ in structure, location, function, and means of activation

Muscle Similarities

• Skeletal and smooth muscle cells are elongated and are called muscle fibers

• Muscle contraction depends on two kinds of myofilaments – actin and myosin

• Muscle terminology is similar

• Sarcolemma – muscle plasma membrane

• Sarcoplasm – cytoplasm of a muscle cell

• Prefixes – myo, mys, and sarco all refer to muscle

Skeletal Muscle Tissues

• Packaged in skeletal muscles that attach to and cover the bony skeleton

• Has obvious stripes called striations

• Is controlled voluntarily (i.e., by conscious control)

• Contracts rapidly but tires easily

• Is responsible for overall body motility

• Is extremely adaptable and can exert forces over a range from a fraction of an ounce to over 70 pounds

Cardiac Muscle Tissue

• Occurs only in the heart

• Is striated like skeletal muscle but is not voluntary

• Contracts at a fairly steady rate set by the heart’s pacemaker

• Neural controls allow the heart to respond to changes in bodily needs

Smooth Muscle Tissue

• Found in the walls of hollow visceral organs, such as the stomach, urinary bladder, and respiratory passages

• Forces food and other substances through internal body channels

• It is not striated and is involuntary

Muscle Function

• Skeletal muscles are responsible for all locomotion

• Cardiac muscle is responsible for coursing the blood through the body

• Smooth muscle helps maintain blood pressure, and squeezes or propels substances (i.e., food, feces) through organs

• Muscles also maintain posture, stabilize joints, and generate heat

Functional Characteristics of Muscles

• Excitability, or irritability – the ability to receive and respond to stimuli

• Contractility – the ability to shorten forcibly

• Extensibility – the ability to be stretched or extended

• Elasticity – the ability to recoil and resume the original resting length

Skeletal Muscle

• Each muscle is a discrete organ composed of muscle tissue, blood vessels, nerve fibers, and connective tissue

• The three connective tissue wrappings are:

• Epimysium – an overcoat of dense regular CT that surrounds the entire muscle

• Perimysium – fibrous CT that surrounds groups of muscle fibers called fascicles

• Endomysium – fine sheath of CT composed of reticular fibers surrounding each muscle fiber

Skeletal Muscle: Nerve and Blood Supply

• Each muscle is served by one nerve, an artery, and one or more veins

• Each skeletal muscle fiber is supplied with a nerve ending that controls contraction

• Contracting fibers require continuous delivery of oxygen and nutrients via arteries

• Wastes must be removed via veins

Skeletal Muscle: Attachments

• Muscles span joints and are attached to bone in at least two places

• When muscles contract the movable bone, the muscle’s insertion moves toward the immovable bone – the muscle’s origin

• Muscles attach:

• Directly – epimysium of the muscle is fused to the periosteum of a bone

• Indirectly – CT wrappings extend beyond the muscle as a tendon or aponeurosis

Microscopic Anatomy of a Skeletal Muscle Fiber

• Each fiber is a long, cylindrical cell with multiple nuclei just beneath the sarcolemma

• Fibers are 10 to 100 mm in diameter, and up to hundreds of centimeters long

• Each cell is a syncytium produced by fusion of embryonic cells

• Sarcoplasm has numerous glycosomes and a unique oxygen-binding protein called myoglobin

• Fibers contain the usual organelles, myofibrils, sarcoplasmic reticulum, and T tubules

Myofibrils

• Myofibrils are densely packed, rodlike contractile elements

• They make up most of the muscle volume

• The arrangement of myofibrils within a fiber is such that a perfectly aligned repeating series of dark A bands and light I bands is evident

Sarcomeres

• The smallest contractile unit of a muscle

• The region of a myofibril between two successive Z discs

• Composed of myofilaments made up of contractile proteins

• Myofilaments are of two types – thick and thin

Myofilaments: Banding Pattern

• Thick filaments – extend the entire length of an A band

• Thin filaments – extend across the I band and partway into the A band

• Z-disc – coin-shaped sheet of proteins (connectins) that anchors the thin filaments and connects myofibrils to one another

• Thin filaments do not overlap thick filaments in the lighter H zone

• M lines appear darker due to the presence of the protein desmin

Ultrastructure of Myofilaments: Thick Filaments

• Thick filaments are composed of the protein myosin

• Each myosin molecule has a rodlike tail and two globular heads

• Tails – two interwoven, heavy polypeptide chains

• Heads – two smaller, light polypeptide chains called cross bridges

Ultrastructure of Myofilaments: Thin Filaments

• Thin filaments are chiefly composed of the protein actin

• Each actin molecule is a helical polymer of globular subunits called G actin

• The subunits contain the active sites to which myosin heads attach during contraction

• Tropomyosin and troponin are regulatory subunits bound to actin

Arrangement of the Filaments in a Sarcomere

• Longitudinal section within one sarcomere

Sarcoplasmic Reticulum (SR)

• SR is an elaborate smooth endoplasmic reticulum that mostly runs longitudinally and surrounds each myofibril

• Paired terminal cisternae form perpendicular cross channels

• Functions in the regulation of intracellular calcium levels

• Elongated tubes called T tubules penetrate into the cell’s interior at each A band–I band junction

• T tubules associate with the paired terminal cisternae to form triads

T Tubules

• T tubules are continuous with the sarcolemma

• They conduct impulses to the deepest regions of the muscle

• These impulses signal for the release of Ca²⁺ from adjacent terminal cisternae

Contraction of Skeletal Muscle Fibers

• Contraction – refers to the activation of myosin’s cross bridges (force generating sites)

• Shortening occurs when the tension generated by the cross bridge exceeds forces opposing shortening

• Contraction ends when cross bridges become inactive, the tension generated declines, and relaxation is induced

Sliding Filament Mechanism of Contraction

• Thin filaments slide past the thick ones so that the actin and myosin filaments overlap to a greater degree

• In the relaxed state, thin and thick filaments overlap only slightly

• Upon stimulation, myosin heads bind to actin and sliding begins

• Each myosin head binds and detaches several times during contraction, acting like a ratchet to generate tension and propel the thin filaments to the center of the sarcomere

• As this event occurs throughout the sarcomeres, the muscle shortens

Role of Ionic Calcium (Ca²⁺) in the Contraction Mechanism

• At low intracellular Ca²⁺ concentration:

• Tropomyosin blocks the binding sites on actin

• Myosin cross bridges cannot attach to binding sites on actin

• The relaxed state of the muscle is enforced

• At higher intracellular Ca²⁺ concentrations:

• Additional calcium binds to troponin (inactive troponin binds two Ca²⁺)

• Calcium-activated troponin binds an additional two Ca²⁺ at a separate regulatory site

• Calcium-activated troponin undergoes a conformational change

• This change moves tropomyosin away from actin’s binding sites

• Myosin head can now bind and cycle

• This permits contraction (sliding of the thin filaments by the myosin cross bridges) to begin

Sequential Events of Contraction

• Cross bridge attachment – myosin cross bridge attaches to actin filament

• Working (power) stroke – myosin head pivots and pulls actin filament toward M line

• Cross bridge detachment – ATP attaches to myosin head and the cross bridge detaches

• “Cocking” of the myosin head – energy from hydrolysis of ATP cocks the myosin head into the high energy state

Regulation of Contraction

• In order to contract, a skeletal muscle must:

• Be stimulated by a nerve ending

• Propagate an electrical current, or action potential, along its sarcolemma

• Have a rise in intracellular Ca²⁺ levels, the final trigger for contraction

• Linking the electrical signal to the contraction is excitation-contraction coupling

Nerve Stimulus of Skeletal Muscle

• Skeletal muscles are stimulated by motor neurons of the somatic nervous system

• Axons of these neurons travel in nerves to muscle cells

• Axons of motor neurons branch profusely as they enter muscles

• Each axonal branch forms a neuromuscular junction with a single muscle fiber

Neuromuscular Junction

• The neuromuscular junction is formed from:

• Axonal endings, which have small membranous sacs (synaptic vesicles) that contain the neurotransmitter acetylcholine (ACh)

• The motor end plate of a muscle, which is a specific part of the sarcolemma that contains ACh receptors that helps form the neuromuscular junction

• Though exceedingly close, axonal ends and muscle fibers are always separated by a space called the synaptic cleft

• When a nerve impulse reaches the end of an axon at the neuromuscular junction:

• Voltage-regulated calcium channels open and allow Ca²⁺ to enter the axon

• Ca²⁺ inside the axon terminal causes axonal vesicles to fuse with the axonal membrane

• This fusion releases ACh into the synaptic cleft via exocytosis

• ACh diffuses across the synaptic cleft to ACh receptors on the sarcolemma

• Binding of ACh to its receptors initiates an action potential in the muscle

Action Potential

• A transient depolarization event that includes polarity reversal of a sarcolemma (or nerve cell membrane) and the propagation of an action potential along the membrane

Action Potential: Electrical Conditions of a Polarized Sarcolemma

• The outside (extracellular) face is positive, while the inside face is negative

• This difference in charge is the resting membrane potential

• The predominant extracellular ion is Na⁺

• The predominant intracellular ion is K⁺

• The sarcolemma is relatively impermeable to both ions

Action Potential: Depolarization and Generation of the Action Potential

• An axonal terminal of a motor neuron releases ACh and causes a patch of the sarcolemma to become permeable to Na⁺ (sodium channels open)

• Na⁺ enters the cell, and the resting potential is decreased (depolarization occurs)

• If the stimulus is strong enough, an action potential is initiated

Action Potential: Propagation of the Action Potential

• Polarity reversal of the initial patch of sarcolemma changes the permeability of the adjacent patch

• Voltage-regulated Na⁺ channels now open in the adjacent patch causing it to depolarize

• Thus, the action potential travels rapidly along the sarcolemma

• Once initiated, the action potential is unstoppable, and ultimately results in the contraction of a muscle

Action Potential: Repolarization

• Immediately after the depolarization wave passes, the sarcolemma permeability changes

• Na⁺ channels close and K⁺ channels open

• K⁺ diffuses from the cell, restoring the electrical polarity of the sarcolemma

• Repolarization occurs in the same direction as depolarization, and must occur before the muscle can be stimulated again (refractory period)

• The ionic concentration of the resting state is restored by the Na⁺-K⁺ pump

Destruction of Acetylcholine

• ACh bound to ACh receptors is quickly destroyed by the enzyme acetylcholinesterase (AChE)

• AChE activity prevents continued muscle fiber contraction in the absence of additional stimuli

Excitation-Contraction Coupling

• Once generated, the action potential:

• Is propagated along the sarcolemma

• Travels down the T tubules

• Triggers Ca²⁺ release from terminal cisternae

• Ca²⁺ binds to troponin and causes:

• The blocking action of tropomyosin to cease

• Actin active binding sites to be exposed

• Myosin cross bridges alternately attach and detach

• Thin filaments move toward the center of the sarcomere

• Hydrolysis of ATP powers this cycling process

• Ca²⁺ is removed into the SR, tropomyosin blockage is restored, and the muscle fiber relaxes

Contraction of Skeletal Muscle (Organ Level)

• Contraction of muscle fibers (cells) and muscles (organs) is similar

• The two types of muscle contractions are:

• Isometric contraction – increasing muscle tension (muscle does not shorten)

• Isotonic contraction – decreasing muscle length (muscle shortens during contraction)

Motor Unit: The Nerve-Muscle Functional Unit

• A motor unit is a motor neuron and all the muscle fibers it supplies

• The number of muscle fibers per motor unit can vary from four to several hundred

• Muscles that control fine movements (fingers, eyes) have small motor units

• Large weight-bearing muscles (thighs, hips) have large motor units

• Muscle fibers from a motor unit are spread throughout the muscle; therefore, contraction of a single motor unit causes weak contraction of the entire muscle

Muscle Twitch

• A muscle twitch is the response of a muscle to a single brief threshold stimulus

• The three phases of a muscle twitch are:

• Latent period – first few milliseconds after stimulation when excitation-contraction coupling is taking place

• Period of contraction – cross bridges actively form and the muscle shortens

• Period of relaxation – Ca²⁺ is reabsorbed into the SR, and muscle tension goes to zero

Graded Muscle Response

• Graded muscle responses are:

• Variations in the degree of muscle contraction

• Required for proper control of skeletal movement

• Responses are graded by:

• Changing the frequency of stimulation

• Changing the strength of the stimulus

Muscle Response to Varying Stimuli

• A single stimulus results in a single contractile response – a muscle twitch

• Frequently delivered stimuli (muscle does not have time to completely relax) increases contractile force – wave summation

• More rapidly delivered stimuli result in incomplete tetanus

• If stimuli are given quickly enough, complete tetanus results

Muscle Response: Stimulation Strength

• Threshold stimulus – the stimulus strength at which the first observable muscle contraction occurs

• Beyond threshold, muscle contracts more vigorously as stimulus strength is increased

• Force of contraction is precisely controlled by multiple motor unit summation

• This phenomenon, called recruitment, brings more and more muscle fibers into play

Treppe: The Staircase Effect

• Staircase – increased contraction in response to multiple stimuli of the same strength

• Contractions increase because:

• There is increasing availability of Ca²⁺ in the sarcoplasm

• Muscle enzyme
systems become
more efficient
because heat is
increased as
muscle contracts

Muscle Tone

• Muscle tone:

• The constant, slightly contracted state of all muscles, which does not produce active movements

• Keeps the muscles firm, healthy, and ready to respond to stimulus

• Spinal reflexes account for muscle tone by:

• Activating one motor unit and then another

• Responding to activation of stretch receptors in muscles and tendons

Isotonic Contractions

• In isotonic contractions, the muscle changes in length (decreasing the angle of the joint) and moves the load

• The two types of isotonic contractions are concentric and eccentric

• Concentric contractions – the muscle shortens and does work

• Eccentric contractions – the muscle contracts as it lengthens

Isometric Contractions

• Tension increases to the muscle’s capacity, but the muscle neither shortens nor lengthens

• Occurs if the load is greater than the tension the muscle is able to develop

Muscle Metabolism: Energy for Contraction

• ATP is the only source used directly for contractile activity

• As soon as available stores of ATP are hydrolyzed (4-6 seconds), they are regenerated by:

• The interaction of ADP with creatine phosphate (CP)

• Anaerobic glycolysis and the Cori cycle

• Aerobic respiration

Muscle Metabolism: Cori Cycle

• When muscle contractile activity reaches 70% of maximum:

• Bulging muscles compress blood vessels

• Oxygen delivery is impaired

• Pyruvic acid is converted into lactic acid

• The lactic acid:

• Diffuses into the bloodstream

• Is picked up and used as fuel by the liver, kidneys, and heart

• Is converted back into pyruvic acid by the liver

Muscle Fatigue

• Muscle fatigue – the muscle is in a state of physiological inability to contract

• Muscle fatigue occurs when:

• ATP production fails to keep pace with ATP use

• There is a relative deficit of ATP, causing contractures

• Lactic acid accumulates in the muscle

• Ionic imbalances are present

Oxygen Debt

• Vigorous exercise causes dramatic changes in muscle chemistry

• For a muscle to return to a resting state:

• Oxygen reserves must be replenished

• Lactic acid must be converted to pyruvic acid

• Glycogen stores must be replaced

• ATP and CP reserves must be resynthesized

• Oxygen debt – the extra amount of O₂ needed for the above restorative processes

Heat Production During Muscle Activity

• Only 40% of the energy released in muscle activity is useful as work

• The remaining 60% is given off as heat

• Dangerous heat levels are prevented by radiation of heat from the skin and sweating

Force of Contraction

• The force of contraction is affected by:

• The number of muscle fibers contracting – the more motor fibers in a muscle, the stronger the contraction

• The relative size of the muscle – the bulkier the muscle, the greater its strength

Force of Contraction

• Series-elastic elements – the noncontractile structures in a muscle

• Degree of muscle stretch – muscles contract strongest when muscle fibers are 80-120% of their normal resting length

Muscle Fiber Type: Functional Characteristics

• Speed of contraction – determined by speed in which ATPases split ATP

• The two types of fibers are slow and fast

• ATP-forming pathways

• Oxidative fibers – use aerobic pathways

• Glycolytic fibers – use anaerobic glycolysis

• These two criteria define three categories – slow oxidative fibers, fast oxidative fibers, and fast glycolytic fibers

Muscle Fibers: Speed of Contraction

• Slow oxidative fibers contract slowly, have slow acting myosin ATPases, and are fatigue resistant

• Fast oxidative fibers contract quickly, have fast myosin ATPases, and have moderate resistance to fatigue

• Fast glycolytic fibers contract quickly, have fast myosin ATPases, and are easily fatigued

Smooth Muscle

• Composed of spindle-shaped fibers with a diameter of 2-10 mm and lengths of several hundred mm

• Lack the coarse CT sheaths of skeletal muscle, but have fine endomysium

• Are organized into two layers (longitudinal and circular) of closely apposed fibers

• Found in walls of hollow organs (except the heart)

• Have essentially the same contractile mechanisms as skeletal muscle

Peristalsis

• When the longitudinal layer contracts, the organ dilates and contracts

• When the circular layer contracts, the organ elongates

• Peristalsis – alternating contractions and relaxations of smooth muscles that mix and squeeze substances through the lumen of hollow organs

Innervation of Smooth Muscle

• Smooth muscle lacks neuromuscular junctions

• Innervating nerves have bulbous swellings called varicosities

• Varicosities release neurotransmitters into wide synaptic clefts called diffuse junctions

Microscopic Anatomy of Smooth Muscle

• SR is less developed than in skeletal muscle and lacks a specific pattern

• T tubules are absent

• Plasma membranes have pouchlike infoldings called caveoli

• Ca²⁺ is sequestered in the extracellular space near the caveoli, allowing rapid influx when channels are opened

• There are no visible striations and no sarcomeres

• Thin and thick filaments are present

Proportion and Organization of Myofilaments in Smooth Muscle

• Ratio of thick to thin filaments is much lower than in skeletal muscle

• Thick filaments have heads along their entire length

• There is no troponin complex

• Thick and thin filaments are arranged diagonally, causing smooth muscle to contract in a corkscrew manner

• Noncontractile intermediate filament bundles attach to dense bodies (analogous to Z discs) at regular intervals

Contraction of Smooth Muscle

• Whole sheets of smooth muscle exhibit slow, synchronized contraction

• They contract in unison, reflecting their electrical coupling with gap junctions

• Action potentials are transmitted from cell to cell

• Some smooth muscle cells:

• Act as pacemakers and set the contractile pace for whole sheets of muscle

• Are self-excitatory and depolarize without external stimuli

Contractile Mechanism

• Actin and myosin interact according to the sliding filament mechanism

• The final trigger for contractions is a rise in intracellular Ca²⁺

• Ca²⁺ is released from the SR and from the extracellular space

• Ca²⁺ interacts with calmodulin and myosin light chain kinase to activate myosin

Role of Calcium Ion

• Ca²⁺ binds to calmodulin and activates it

• Activated calmodulin activates the kinase enzyme

• Activated kinase transfers phosphate from ATP to myosin cross bridges

• Phosphorylated cross bridges interact with actin to produce shortening

• Smooth muscle relaxes when intracellular Ca²⁺ levels drop

Special Features of Smooth Muscle Contraction

• Unique characteristics of smooth muscle include:

• Smooth muscle tone

• Slow, prolonged contractile activity

• Low energy requirements

• Response to stretch

Response to Stretch

• Smooth muscles exhibits a phenomenon called stress-relaxation response in which:

• Smooth muscle responds to stretch only briefly, and then adapts to its new length

• The new length, however, retains its ability to contract

• This enables organs such as the stomach and bladder to temporarily store contents

Hyperplasia

• Certain smooth muscles can divide and increase their numbers by undergoing hyperplasia

• This is shown by estrogen’s effect on the uterus

• At puberty, estrogen stimulates the synthesis of more smooth muscle, causing the uterus to grow to adult size

• During pregnancy, estrogen stimulates uterine growth to accommodate the increasing size of the growing fetus

Types of Smooth Muscle: Single Unit

• The cells of single unit smooth muscle, commonly called visceral muscle:

• Contract rhythmically as a unit

• Are electrically coupled to one another via gap junctions

• Often exhibit spontaneous action potentials

• Are arranged in opposing sheets and exhibit stress-relaxation response

Types of Smooth Muscle: Multiunit

• Multiunit smooth muscles are found:

• In large airways to the lungs

• In large arteries

• In arrector pili muscles

• Attached to hair follicles

• In the internal eye muscles

Types of Smooth Muscle: Multiunit

• Their characteristics include:

• Rare gap junctions

• Infrequent spontaneous depolarizations

• Structurally independent muscle fibers

• A rich nerve supply, which, with a number of muscle fibers, forms motor units

• Graded contractions in response to neural stimuli

Muscular Dystrophy

• Muscular dystrophy – group of inherited muscle-destroying diseases where muscles enlarge due to fat and connective tissue deposits, but muscle fibers atrophy

• Duchenne muscular dystrophy (DMD)

• Inherited, sex-linked disease carried by females and expressed in males (1/3500)

• Diagnosed between the ages of 2-10

• Victims become clumsy and fall frequently as their muscles fail

• Progresses from the extremities upward, and victims die of respiratory failure in their 20s

• Caused by a lack of the cytoplasmic protein dystrophin

• There is no cure, but myoblast transfer therapy shows promise

Homeostatic Imbalance: Age Related

• With age, connective tissue increases and muscle fibers decrease

• Muscles become stringier and more sinewy

• By age 80, 50% of muscle mass is lost (sarcopenia)

• Regular exercise reverses sarcopenia

• Aging of the cardiovascular system affects every organ in the body

• Atherosclerosis may block distal arteries, leading to intermittent claudication and causing severe pain in leg muscles

Developmental Aspects

• Muscle tissue develops from embryonic mesoderm called myoblasts

• Multinucleated skeletal muscles form by fusion of myoblasts

• The growth factor agrin stimulates the clustering of ACh receptors at newly forming motor end plates

• As muscles are brought under the control of the somatic nervous system, the numbers of fast and slow fibers are also determined

• Cardiac and smooth muscle myoblasts

• Do not fuse but develop gap junctions at an early embryonic stage

Developmental Aspects: Regeneration

• Cardiac and skeletal muscle become amitotic, but can lengthen and thicken

• Myoblastlike satellite cells show very limited regenerative ability

• Cardiac cells lack satellite cells

• Smooth muscle has good regenerative ability

Developmental Aspects: After Birth

• Muscular development reflects neuromuscular coordination

• Development occurs head-to-toe, and proximal-to-distal

• Peak natural neural control of muscles is achieved by midadolescence

• Athletics and training can improve neuromuscular control

Developmental Aspects: Male and Female

• There is a biological basis for greater strength in men than in women

• Women’s skeletal muscle makes up 36% of their body mass

• Men’s skeletal muscle makes up 42% of their body mass

• These differences are due primarily to the male sex hormone testosterone

• With more muscle mass, men are generally stronger than women

• Body strength per unit muscle mass, however, is the same