Human Anatomy and Physiology - Muscle Tissue

Overview of Muscle Tissue

• Nearly half of the body's mass is muscle tissue.
• Muscle tissue transforms chemical energy (ATP) into directed mechanical energy to exert force.
• Prefixes for muscle: Myo, mys, and sarco (e.g., sarcoplasm: muscle cell cytoplasm).
• Three types of muscle tissue:
  • Skeletal
  • Cardiac
  • Smooth
• Only skeletal and smooth muscle cells are elongated and referred to as muscle fibers.

Types of Muscle Tissue

• Skeletal muscle: Attached to bones and skin; voluntary (consciously controlled); contracts rapidly, tires easily, powerful.
• Cardiac muscle: Found only in the heart; involuntary (not consciously controlled).
• Smooth muscle: Found in walls of hollow organs; involuntary (not consciously controlled).

Characteristics of Muscle Tissue

• Four main characteristics:
  • Excitability (responsiveness): Ability to receive and respond to stimuli.
  • Contractility: Ability to shorten forcibly when stimulated.
  • Extensibility: Ability to be stretched.
  • Elasticity: Ability to recoil to resting length.
• Four important functions:
  • Produce movement: Responsible for locomotion and manipulation (e.g., walking, digesting, pumping blood).
  • Maintain posture and body position.
  • Stabilize joints.
  • Generate heat as they contract.

Skeletal Muscle Anatomy

• Skeletal muscle is an organ made up of different tissues with three features: nerve and blood supply, connective tissue sheaths, and attachments.
• Each muscle receives a nerve, artery, and veins.
  • Consciously controlled skeletal muscle has nerves supplying every fiber to control activity.
• Contracting muscle fibers require huge amounts of oxygen and nutrients and need waste products removed quickly.

Connective Tissue Sheaths

• Each skeletal muscle, as well as each muscle fiber, is covered in connective tissue.
• Support cells and reinforce whole muscle.
• Sheaths from external to internal:
  • Epimysium: Dense irregular connective tissue surrounding entire muscle; may blend with fascia.
  • Perimysium: Fibrous connective tissue surrounding fascicles (groups of muscle fibers).
  • Endomysium: Fine areolar connective tissue surrounding each muscle fiber.

Attachments

• Muscles span joints and attach to bones.
• Muscles attach to bone in at least two places:
  • Insertion: Attachment to movable bone.
  • Origin: Attachment to immovable or less movable bone.
• Attachments can be direct or indirect:
  • Direct (fleshy): Epimysium fused to periosteum of bone or perichondrium of cartilage.
  • Indirect: Connective tissue wrappings extend beyond muscle as ropelike tendon or sheetlike aponeurosis.

Muscle Fiber Microanatomy and Sliding Filament Model

• Skeletal muscle fibers are long, cylindrical cells that contain multiple nuclei.
• Sarcolemma: Muscle fiber plasma membrane.
• Sarcoplasm: Muscle fiber cytoplasm.
• Contains many glycosomes for glycogen storage, as well as myoglobin for O_2 storage.
• Modified organelles:
  • Myofibrils
  • Sarcoplasmic reticulum
  • T tubules

Myofibrils

• Myofibrils are densely packed, rodlike elements.
  • A single muscle fiber can contain 1000s.
  • Accounts for ~80% of muscle cell volume.
• Myofibril features:
  • Striations
  • Sarcomeres
  • Myofilaments
  • Molecular composition of myofilaments

Myofibrils: Striations and Sarcomeres

• Striations: Stripes formed from repeating series of dark and light bands along length of each myofibril.
  • A bands: Dark regions.
    • H zone: Lighter region in middle of dark A band.
    • M line: Line of protein (myomesin) that bisects H zone vertically.
  • I bands: Lighter regions.
    • Z disc (line): Coin-shaped sheet of proteins on midline of light I band.
• Sarcomere
  • Smallest contractile unit (functional unit) of muscle fiber.
  • Contains A band with half of an I band at each end.
    • Consists of area between Z discs
  • Individual sarcomeres align end to end along myofibril, like boxcars of train.

Myofibrils: Myofilaments

• Myofilaments
  • Orderly arrangement of actin and myosin myofilaments within sarcomere
  • Actin myofilaments: thin filaments
    • Extend across I band and partway in A band
    • Anchored to Z discs
  • Myosin myofilaments: thick filaments
    • Extend length of A band
    • Connected at M line
  • Sarcomere cross section shows hexagonal arrangement of one thick filament surrounded by six thin filaments

Clinical - Homeostatic Imbalance 9.1

• Duchenne muscular dystrophy (DMD) is most common and serious form of muscular dystrophies, muscle-destroying diseases that generally appear during childhood
• Inherited as a sex-linked recessive disease, so almost exclusively in males (1 in 3600 births)
• Appears between 2 and 7 years old when boy becomes clumsy and falls frequently
• Disease progresses from extremities upward, finally affecting head, chest muscles, and cardiac muscle.
• With supportive care, people with DMD can live into 30s and beyond

Sarcoplasmic Reticulum and T Tubules

• Sarcoplasmic reticulum: Network of smooth endoplasmic reticulum tubules surrounding each myofibril.
  • Most run longitudinally
  • Terminal cisterns form perpendicular cross channels at the A–I band junction
  • SR functions in regulation of intracellular Ca^{2+} levels
  • Stores and releases Ca^{2+}
• T tubules
  • Tube formed by protrusion of sarcolemma deep into cell interior
    • Increase muscle fiber’s surface area greatly
    • Lumen continuous with extracellular space
    • Allow electrical nerve transmissions to reach deep into interior of each muscle fiber
  • Tubules penetrate cell’s interior at each A–I band junction between terminal cisterns
    • Triad: area formed from terminal cistern of one sarcomere, T tubule, and terminal cistern of neighboring sarcomere

Sliding Filament Model of Contraction

• Contraction: the activation of cross bridges to generate force
• Shortening occurs when tension generated by cross bridges on thin filaments exceeds forces opposing shortening
• Contraction ends when cross bridges become inactive
• In the relaxed state, thin and thick filaments overlap only slightly at ends of A band
• Sliding filament model of contraction states that during contraction, thin filaments slide past thick filaments, causing actin and myosin to overlap more
  • Neither thick nor thin filaments change length, just overlap more
• When nervous system stimulates muscle fiber, myosin heads are allowed to bind to actin, forming cross bridges, which cause sliding (contraction) process to begin

Sliding Filament Model Details

• Cross bridge attachments form and break several times, each time pulling thin filaments a little closer toward center of sarcomere in a ratcheting action
  • Causes shortening of muscle fiber
• Z discs are pulled toward M line
• I bands shorten
• Z discs become closer
• H zones disappear
• A bands move closer to each other

Muscle Fiber Contraction Background and Overview

• Decision to move is activated by brain, signal is transmitted down spinal cord to motor neurons which then activate muscle fibers
• Neurons and muscle cells are excitable cells capable of action potentials
  • Excitable cells are capable of changing resting membrane potential voltages
• AP crosses from neuron to muscle cell via the neurotransmitter acetylcholine (ACh)
• Ion Channels
  • Play the major role in changing of membrane potentials
  • Two classes of ion channels:
    • Chemically gated ion channels – opened by chemical messengers such as neurotransmitters
      • Example: ACh receptors on muscle cells
    • Voltage-gated ion channels – open or close in response to voltage changes in membrane potential

Anatomy of Motor Neurons and the Neuromuscular Junction

• Skeletal muscles are stimulated by somatic motor neurons
• Axons (long, threadlike extensions of motor neurons) travel from central nervous system to skeletal muscle
• Each axon divides into many branches as it enters muscle
• Axon branches end on muscle fiber, forming neuromuscular junction or motor end plate
  • Each muscle fiber has one neuromuscular junction with one motor neuron
• Axon terminal (end of axon) and muscle fiber are separated by gel-filled space called synaptic cleft
• Stored within axon terminals are membrane-bound synaptic vesicles
  • Synaptic vesicles contain neurotransmitter acetylcholine (ACh)
• Infoldings of sarcolemma, called junctional folds, contain millions of ACh receptors
• NMJ consists of axon terminals, synaptic cleft, and junctional folds

Events at the Neuromuscular Junction

• AP arrives at axon terminal
• Voltage-gated calcium channels open, calcium enters motor neuron
• Calcium entry causes release of ACh neurotransmitter into synaptic cleft
• ACh diffuses across to ACh receptors (Na^+ chemical gates) on sarcolemma
• ACh binding to receptors, opens gates, allowing Na^+ to enter resulting in end plate potential
• Acetylcholinesterase degrades ACh

Clinical - Homeostatic Imbalance 9.2

• Many toxins, drugs, and diseases interfere with events at the neuromuscular junction
  • Example: myasthenia gravis: disease characterized by drooping upper eyelids, difficulty swallowing and talking, and generalized muscle weakness
    • Involves shortage of Ach receptors because person’s ACh receptors are attacked by own antibodies
    • Suggests this is an autoimmune disease

Generation of an Action Potential Across the Sarcolemma

• Resting sarcolemma is polarized, meaning a voltage exists across membrane
  • Inside of cell is negative compared to outside
• Action potential is caused by changes in electrical charges
• Occurs in three steps
  • Generation of end plate potential
  • Depolarization
  • Repolarization

End Plate Potential

• ACh released from motor neuron binds to ACh receptors on sarcolemma
• Causes chemically gated ion channels (ligands) on sarcolemma to open
• Na^+ diffuses into muscle fiber.
  • Some K^+ diffuses outward, but not much
• Because Na^+ diffuses in, interior of sarcolemma becomes less negative (more positive)
• Results in local depolarization called end plate potential

Depolarization

• Depolarization: generation and propagation of an action potential (AP)
• If end plate potential causes enough change in membrane voltage to reach critical level called threshold, voltage-gated Na^+ channels in membrane will open
• Large influx of Na^+ through channels into cell triggers AP that is unstoppable and will lead to muscle fiber contraction
• AP spreads across sarcolemma from one voltage-gated Na^+ channel to next one in adjacent areas, causing that area to depolarize

Repolarization

• Repolarization: restoration of resting conditions
• Na^+ voltage-gated channels close, and voltage-gated K^+ channels open
• K^+ efflux out of cell rapidly brings cell back to initial resting membrane voltage
• Refractory period: muscle fiber cannot be stimulated for a specific amount of time, until repolarization is complete
• Ionic conditions of resting state are restored by Na^+-K^+ pump
  • Na^+ that came into cell is pumped back out, and K^+ that flowed outside is pumped back into cell

Excitation-Contraction (E-C) Coupling

• Excitation-Contraction (E-C) Coupling is the Sequence of Events by Which Transmission of an Action Potential Along the Sarcolemma Leads to the Sliding of Myofilaments

Muscle Fiber Contraction: Cross Bridge Cycling

• At low intracellular Ca^{2+} concentration:
  • Tropomyosin blocks active sites on actin
  • Myosin heads cannot attach to actin
  • Muscle fiber remains relaxed
• Voltage-sensitive proteins in T tubules change shape, causing sarcoplasmic reticulum (SR) to release Ca^{2+} to cytosol
• At higher intracellular Ca^{2+} concentrations, Ca^{2+} binds to troponin
• Troponin changes shape and moves tropomyosin away from myosin-binding sites
• Myosin heads is then allowed to bind to actin, forming cross bridge
• Cycling is initiated, causing sarcomere shortening and muscle contraction
• When nervous stimulation ceases, Ca^{2+} is pumped back into SR, and contraction ends

Cross Bridge Cycle Steps

• Four steps of the cross bridge cycle
  • Cross bridge formation: high-energy myosin head attaches to actin thin filament active site
  • Working (power) stroke: myosin head pivots and pulls thin filament toward M line
  • Cross bridge detachment: ATP attaches to myosin head, causing cross bridge to detach
  • Cocking of myosin head: energy from hydrolysis of ATP “cocks” myosin head into high-energy state
    • This energy will be used for power stroke in next cross bridge cycle

Clinical - Homeostatic Imbalance 9.3 (Rigor Mortis)

• Rigor mortis
  • 3–4 hours after death, muscles begin to stiffen
    • Peak rigidity occurs about 12 hours postmortem
  • Intracellular calcium levels increase because ATP is no longer being synthesized, so calcium cannot be pumped back into SR
    • Results in cross bridge formation
  • ATP is also needed for cross bridge detachment
    • Results in myosin head staying bound to actin, causing constant state of contraction
  • Muscles stay contracted until muscle proteins break down, causing myosin to release

The Motor Unit

• A Motor Unit Consists of One Motor Neuron and All The Muscle Fibers it Innervates

Graded Muscle Response

• Muscle response to changes in stimulus strength
  • Recruitment (or multiple motor unit summation): stimulus is sent to more muscle fibers, leading to more precise control
  • Types of stimulus involved in recruitment:
    • Subthreshold stimulus: stimulus not strong enough, so no contractions seen
    • Threshold stimulus: stimulus is strong enough to cause first observable contraction
    • Maximal stimulus: strongest stimulus that increases maximum contractile force
      • All motor units have been recruited

Recruitment and Size Principle

• Muscle response to changes in stimulus strength
• Recruitment works on size principle
  • Motor units with smallest muscle fibers are recruited first
  • Motor units with larger and larger fibers are recruited as stimulus intensity increases
  • Largest motor units are activated only for most powerful contractions
  • Motor units in muscle usually contract asynchronously
    • Some fibers contract while others rest
    • Helps prevent fatigue

Muscle Tone

• Constant, slightly contracted state of all muscles
• Due to spinal reflexes
  • Groups of motor units are alternately activated in response to input from stretch receptors in muscles
• Keeps muscles firm, healthy, and ready to respond

Isotonic and Isometric Contractions

• Isotonic contractions: muscle changes in length and moves load
  • Isotonic contractions can be either concentric or eccentric:
    • Concentric contractions: muscle shortens and does work
      • Example: biceps contract to pick up a book
    • Eccentric contractions: muscle lengthens and generates force
      • Example: laying a book down causes biceps to lengthen while generating a force
• Isometric contractions
  • Load is greater than the maximum tension muscle can generate, so muscle neither shortens nor lengthens
• Electrochemical and mechanical events are same in isotonic or isometric contractions, but results are different
  • In isotonic contractions, actin filaments shorten and cause movement
  • In isometric contractions, cross bridges generate force, but actin filaments do not shorten
    • Myosin heads “spin their wheels” on same actin-binding site

Energy for Contraction and ATP

• ATP supplies the energy needed for the muscle fiber to:
  • Move and detach cross bridges
  • Pump calcium back into SR
  • Pump Na^+ out of and K^+ back into cell after excitation-contraction coupling
• Available stores of ATP depleted in 4–6 seconds
• ATP is the only source of energy for contractile activities; therefore it must be regenerated quickly

Anaerobic Pathway: Glycolysis and Lactic Acid Formation

• ATP can also be generated by breaking down and using energy stored in glucose
  • Glycolysis: first step in glucose breakdown
    • Does not require oxygen
    • Glucose is broken into 2 pyruvic acid molecules
    • 2 ATPs are generated for each glucose broken down
• Anaerobic pathway: glycolysis and lactic acid formation
  • Lactic acid
    • Diffuses into bloodstream
    • Used as fuel by liver, kidneys, and heart
    • Converted back into pyruvic acid or glucose by liver
• Anaerobic respiration yields only 5% as much ATP as aerobic respiration, but produces ATP 2½ times faster

Muscle Fatigue

• Fatigue is the physiological inability to contract despite continued stimulation
• Possible causes include:
  • Ionic imbalances can cause fatigue
    • Levels of K^+, Na^+ and Ca^{2+} can change disrupting membrane potential of muscle cell
  • Increased inorganic phosphage (Pi) from CP and ATP breakdown may interfere with calcium release from SR or hamper power
  • Decreased ATP and increased magnesium
    • As ATP levels drop, magnesium levels increase and this can interfere with voltage sensitive T tubule proteins
  • Decreased glycogen
• Lack of ATP is rarely a reason for fatigue, except in severely stressed muscles

Factors of Muscle Contraction Force

• Force of contraction depends on number of cross bridges attached, which is affected by four factors:
  • Number of muscle fibers stimulated (recruitment): the more motor units recruited, the greater the force.
  • Relative size of fibers: the bulkier the muscle, the more tension it can develop
    • Muscle cells can increase in size (hypertrophy) with regular exercise
  • Frequency of stimulation: the higher the frequency, the greater the force
    • Stimuli are added together
  • Degree of muscle stretch: muscle fibers with sarcomeres that are 80–120% their normal resting length generate more force
    • If sarcomere is less than 80% resting length, filaments overlap too much, and force decreases
    • If sarcomere is greater than 120% of resting length, filaments do not overlap enough so force decreases

Velocity and Duration of Contraction

• How fast a muscle contracts and how long it can stay contracted is influenced by:
  • Muscle fiber type
  • Load
  • Recruitment
• Muscle fiber type
  • Classified according to two characteristics
    • Speed of contraction – slow or fast fibers according to:
      • Speed at which myosin ATPases split ATP
      • Pattern of electrical activity of motor neurons
    • Metabolic pathways used for ATP synthesis
      • Oxidative fibers: use aerobic pathways
      • Glycolytic fibers: use anaerobic glycolysis

Muscle Fiber Types

• Based on these two criteria, skeletal muscle fibers can be classified into three types:
  • Slow oxidative fibers, fast oxidative fibers, or fast glycolytic fibers
• Most muscles contain mixture of fiber types, resulting in a range of contractile speed and fatigue resistance
  • All fibers in one motor unit are the same type
  • Genetics dictate individual’s percentage of each
• Different muscle types are better suited for different jobs
  • Slow oxidative fibers: low-intensity, endurance activities
    • Example: maintaining posture
  • Fast oxidative fibers: medium-intensity activities
    • Example: sprinting or walking
  • Fast glycolytic fibers: short-term intense or powerful movements
    • Example: hitting a baseball

Clinical - Homeostatic Imbalance 9.4 (Muscle Atrophy)

• Muscles must be active to remain healthy
• Disuse atrophy (degeneration and loss of mass)
  • Due to immobilization or loss of neural stimulation
  • Can begin almost immediately.
• Muscle strength can decline 5% per day
• Paralyzed muscles may atrophy to one-fourth initial size
• Fibrous connective tissue replaces lost muscle tissue
• Rehabilitation is impossible at this point

Smooth Muscle

• Found in walls of most hollow organs:
  • Respiratory, digestive, urinary, reproductive, circulatory (except in smallest of blood vessels) except heart
  • Not found in heart – heart contains cardiac muscle, not smooth
• Most smooth muscle organized into sheets of tightly packed fibers

Contraction of Smooth Muscle

• Mechanism of contraction
  • Slow, synchronized contractions
  • Cells electrically coupled by gap junctions
    • Action potentials transmitted from fiber to fiber
  • Some cells are self-excitatory (depolarize without external stimuli)
    • Act as pacemakers for sheets of muscle
    • Rate and intensity of contraction may be modified by neural and chemical stimuli
• Contraction in smooth muscle is similar to skeletal muscle contraction in following ways:
  • Actin and myosin interact by sliding filament mechanism
  • Final trigger is increased intracellular Ca^{2+} level
  • ATP energizes sliding process
  • Contraction stops when Ca^{2+} is no longer available

Smooth Muscle Contraction Differences

• Contraction in smooth muscle is different from skeletal muscle in following ways:
  • Some Ca^{2+} still obtained from SR, but mostly comes from extracellular space
  • Ca^{2+} binds to calmodulin, not troponin
  • Activated calmodulin then activates myosin kinase (myosin light chain kinase)
  • Activated myosin kinase phosphorylates myosin head, activating it
    • Leads to crossbridge formation with actin
• Stopping smooth muscle contraction requires more steps than skeletal muscle
  • Relaxation requires:
    • Ca^{2+} detachment from calmodulin
    • Active transport of Ca^{2+} into SR and extracellularly
    • Dephosphorylation of myosin to inactive myosin

Developmental Aspects of Muscle

• All muscle tissues develop from embryonic myoblasts
• Multinucleated skeletal muscle cells form by fusion of many myoblasts
• Cardiac and smooth muscle myoblasts do not fuse, but develop gap junctions
  • Cardiac muscle cells start pumping when embryo is 3 weeks old
• Regeneration of muscle:
  • Myoblast-like skeletal muscle satellite cells have limited regenerative ability
  • Cardiomyocytes can divide at modest rate, but injured heart muscle is mostly replaced by connective tissue
  • Smooth muscle regenerates throughout life
• Cardiac and skeletal muscle can lengthen and thicken in growing child
  • In adults, leads to hypertrophy
• Muscular development in infants reflects neuromuscular coordination
  • Development occurs head to toe, and proximal to distal
    • A baby can lift its head before it is able to walk
• Peak natural neural control occurs by midadolescence
  • Athletics and training can continue to improve neuromuscular control

Muscle Mass and Aging

• Difference in muscle mass between sexes:
  • Female skeletal muscle makes up 36% of body mass
  • Male skeletal muscle makes up 42% of body mass, primarily as a result of testosterone
    • Males have greater ability to enlarge muscle fibers, also because of testosterone
  • Body strength per unit muscle mass is the same in both sexes
• Aging muscles:
  • With age, connective tissue increases, and muscle fibers decrease
  • By age 30, loss of muscle mass (sarcopenia) begins
  • Regular exercise reverses sarcopenia
  • Atherosclerosis may block distal arteries, leading to intermittent claudication (limping) and severe pain in leg muscles