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