Muscle Physiology

The three muscles types

1. Striated Cardiac Muscle

2. Striated Skeletal Muscle

3. Smooth Muscle

Skeletal Muscle Disorders: Myopathies

INHERITED MYOPATHIES

• Congenital myopathies

• Muscular dystrophies (e.g. Duchenne)

• Metabolic myopathies (e.g. glycogen storage diseases such as McArdle and Pompe diseases)

• Mitochondrial myopathies

• Channelopathies

ACQUIRED MYOPATHIES

• Autoimmune/inflammatory myopathies (e.g. Dermatomyositis)

• Toxic myopathies (e.g. caused by statins)

• Endocrine myopathies

• Infectious myopathies

• Critical illness myopathy (complication in critical care)

Neuromuscular junction disorder

• Primary cause: Communication between the nerve and muscle is disrupted

• Secondary: Affects muscle

• Examples:

  • Congenital myasthenic syndromes (genetic disorder)

  • Myasthenia gravis (autoimmune disorder)

  • Botulism toxin

Neurogenic atrophy

• Primary cause: Nerve disorder or damage

• Secondary: Affects muscle

• Examples:

  • Nerve and spinal cord injuries

  • Motor neuron diseases (brain and spinal cord motor nerves die prematurely)

  • Sensory and autonomic neuropathies (affect sensory involuntary functions)

  • Nerve tumours

Sacropenia

• Loss of skeletal muscle mass (atrophy) with aging

• Muscle mass peaks between 25 and 30 years

• Usually, 0.5 to 1% per year after the age of 50 years

• By the age of 65 years muscle mass is reduced by approximately 25 to 30%

• Extent of atrophy is muscle specific and is influence by several factors such as muscle activity

• Results in a decrease of muscle strength and power

Skeletal muscle

• 660 muscles in adult human

• Constitutes to 45% of our body weight

Functions of skeletal muscle

1. Converts chemical energy into force and mechanical work (movement and locomotion)

2. Maintains posture and body position.

3. Support soft tissues (abdominal wall, floor of the pelvic cavity)

4. Encircle openings of the digestive and urinary tracts

5. Heat production.

6. Reservoir for protein storage

MTU (Musculotendinous Unit)

• The (musculotendinous unit) draws one articulating bone toward the other

• Origin – the attachment to the stationary bone (or the bone that moves the least)

• Insertion – the attachment to the moveable bone (or the bone that moves the most)

Types of levers

• Class 1: Effort - Fulcrum - Load (seesaw)

• Class 2: Effort - Load - Fulcrum (wheelbarrow)

• Class 3: Fulcrum - Effort - Load (tweezzer)

Muscle architecture

1. Muscle

2. Muscle fascicle

3. Muscle fibre/cell / myofibre

4. Myofibril

5. Sarcomere

6. Myofilaments

Three layers of connective tissue around skeletal muscle

1. Epimysium = a sheath of dense irregular connective tissue, covers each muscle.

   • This allows the muscle to contract and move while maintaining structural integrity

   • Separates individual muscles from each other and other structures.

   • Allows for independent movement

2. Perimysium = covers fascicles (10 to 100 muscle fibres per fascicle)

3. Endomysium = covers each muscle fibre (cell) forming the basement membrane.

Skeletal Muscle Fibre (Cell)

• Skeletal muscle fibres are highly differentiated elongated multinucleated (200-300 nuclei/mm).

• Post-mitotic - therefore muscle fibres are unable to divide to repair muscle tissue

• Fast twitch fibre diameter > slow twitch.

Skeletal Muscle Fibre Types

SLOW TWITCH:

• Type 1: Slow Oxidative (SO) - red fibre

FAST TWITCH:

• 2A: Fast Oxidative Glycolytic (FOG) - red fibre

• 2X: Fast Glycolytic (FG) - white fibre

• 2B

*in red fibres there is high myoglobin and mitochondria content

Muscle architecture

1. Myofibre (Cell)

2. Myofibrils

3. Myofilaments (Protein filaments)

Myofibrils

• Each muscle fibre (cell) is densely packed with myofibrils

• Myofibrils run in parallel rows from one end of the muscle fiber to the other

• Other organelles are restricted to the narrow cytoplasmic spaces that remain between adjacent myofibrils

• Each myofibril contains myosin (thick) and actin (thin) filament AKA myofilaments

• Thick and thin filaments overlap causing striated appearance (banding pattern)

• Repeating I (light) and A (dark) bands along the myofibril

• The functional unit of muscle contraction (sarcomere) is located between two Z discs

Sarcomere

• Repeating functional unit within the myofibril of skeletal muscle cells

• Divided into the I band (2 halves), A band, H-zone, M line (located in the middle of the sarcomere where it bisects the A band and H zone) and Z line (bisects the I band and is the structure between adjacent sarcomeres)

• Made from two fibres: thin and thick which are called actin and myosin

I (Light) Band

• Consists of only thin (actin) filaments

• Shortens during contraction due to the increasing overlap of actin and myosin filaments

A (Dark) Band

• Contains both thin (actin) and thick (myosin) filaments

• The myosin and actin filaments overlap in peripheral regions of the A band

• the middle region (called the H zone) contains only myosin filaments

• Remains the same size during muscle contraction

H Zone

• The central region of the A band

• Contains only thick (myosin) filaments

• Shortens during contraction due to the increasing overlap of actin and myosin filaments

• No longer visible when the muscle is fully contracted

Sarcoplasmic Reticulum (SR)

• The sarcoplasmic reticulum (SR) is a modified smooth ER

• Consist of interconnected sacs and tubes that surround each myofibril

• At the end of each SR there is an expanded portion known as terminal cisternae

• Two terminal cisternae for each SR

• Stores Ca2+ - used for muscle contraction

• Most of the Ca2+ is stored in the terminal cisternae in the relaxed muscle

• [Ca2+] is higher in SR compared to cytoplasm

• SR membrane contains Ca2+ calcium release channels called ryanodine receptors (RyRs)

Transverse Tubules (T-Tubules)

• Terminal cisternae of adjacent SRs are separated by only a very narrow gap

• Gap contains the transverse tubules (T-tubules)

• T-tubules are extensions of the sarcolemma that enter the cell

• Contain extra-cellular fluid

• The internal membranes of the Ttubules are extensions of the sarcolemma

• They contain voltage-gated Ca2+ channels - dihydropyridine (DHP) receptor

• T-tubule allow action potentials to moves into the interior of the muscle cell

• The structure where a T-tubule and two terminal cisternae meet are called a triad

Mitochondria

• Mitochondria are found just beneath the plasma membrane and between the myofibrils

• Oxidative enzymes are found in the mitochondria

• More mitochondria in slow twitch muscle

• Endurance training may double the mitochondrial content

Sliding Filament Theory

• Thin filaments slide over the thick filaments resulting in shortening of the the sarcomere and muscle

• ATP hydrolysis and Ca2+ required

• Myosin heads bend back and forth step by step (cross bridge cycle)

• Z discs move towards each other

• The myofilaments do not change length, merely slide over one another

• Width of A band remains constant

• Width of the I band and H zone changes

• Shortening of all sarcomeres results is muscle shortening

Thin Filament (Actin) Structure

Actin filaments consist of three proteins:

• One structural:

  • Actin

• Two regulatory:

  • Tropomyosin

  • Troponin

• Actin monomers form a double stranded filament

• Actin has a myosin-binding site

• Troponin is able to bind Ca2+

• In relaxed muscle, the tropomyosin physically covers the myosin-binding site of the of actin filament

• Troponin and tropomyosin work together to regulate the binding to actin to myosin

Myosin binding site

• a specific region on the actin protein where the myosin head can attach, forming a cross-bridge

• it allows myosin to pull on the actin filaments, causing them to slide past each other

Thick (Myosin) Filament Structure

• Major component of thick filaments within the sarcomere

• Large protein with a molecular weight of 500 kDa

• Thin rod-like molecule (200 nm long; 2-3 nm Diameter)

• Different isoforms: MHC1, MHC2A, MHC2X

• Myosin is a hexamer consisting of

• 2 identical myosin heavy chains (MHC) of about 220 kDa each

• 2 pairs of (i.e. 4) non-identical myosin light chains (MLC)

Assembled Thick Filament

• approx. 300 molecules of myosin in one thick filament

• The thin rod-like tails overlap to form the thick filament with the heads protruding out of the filament

Cross-Bridge between the Thick and Thin Filaments

• the myosin head of the thick filament binds to the actin (thin filament) during muscle contraction, forming a connection that allows the filaments to slide past each other, resulting in muscle shortening

T-Tubule and Sarcoplasmic Reticulum (muscle fibre depolarization)

• Muscle fibre depolarization starts at the motor end plate

• Action potential (AP) transmitted along the sarcolemma

• AP descends into the fibre via the T-tubules

• Depolarization of the Ttubule membrane

• Ca2+ channels open in the SR cisternae

• Rapid release of Ca2+ from sarcoplasmic reticulum (SR)

WHY:

• because it triggers the release of calcium ions, which are the key initiators of the contraction process

Cross-Bridge Motion

• Released Ca2+ binds to troponin C (TnC)

• Troponin-tropomyosin complexes rotate

• Uncovering of myosin-binding sites on actin

• Myosin head binds actin to form a cross-bridge

• Myosin head moves 45 degrees

• Pulling the actin filament towards the M line (±12 nm)

Cross-Bridge Cycle

1. Resting fibre, cross-bridge not attached to actin

2. Cross-bridge binds to actin (Pi is released)

3. Power stroke causes filaments to slide

4. A new ATP binds to the myosin head allowing it to release from actin

5. ATP is hydrolysed, causing cross-bridge to return to its original orientation

Sarcomere Length-Tension Relationship

• cross-bridge formation responsible for force generation

• there is a direct relationship between the force developed by a muscle and the number of overlapping cross-bridges

Sequence of events in skeletal muscle relaxation

• Ca2+ pumped back into sarcoplasmic reticulum

• Active (ATP) dependent process

• Release of Ca2+ from troponin

• Cessation of interaction between actin and myosin

IF Inhibit active transport of Ca2+:

• Relaxation does not occur

• Even if there are no more action potentials

ATP provides energy for both?

• Contraction (cross-bridge cycle)

• Relaxation (active transport of calcium into SR)

Effects of Muscle Architecture on Force Production and Shortening Velocity

• An increase in the number of sarcomeres in series within a myofibril causes an increase in the overall velocity of shortening of the fibre

• The sarcomeres arranged in parallel to each other, the greater the capacity for maximum force production (less shortening velocity)

Skeletal Muscle Motor Unit Innervation

• The minimum functional unit of neural control of muscle

  contraction is called the motor unit

• A motor unit consists of:-

  1. a cell body

  2. the outgrowing (alpha) α-motor neuron (axon,

  efferent nerve, “movement” nerve)

  3. Muscle fibres it innervates

• The number of muscle cells in a single motor unit ranges

  (known as the innervation ratio)

• When an action potential is propagated in a single axon all the fibres in the motor unit are stimulated to contract

Motor units in skeletal muscle

• each individual motor unit consists of the sample fibre types

• groups of motor units work together to coordinate the contractions of a single muscle

• force of muscle contraction is controlled by the number of activated motor units

Motor units recruitment and force production

• increase contraction force by increasing the number of motor units

• smaller units recruited first

• larger units are then added

• individual motor units are responsible for each contraction and occur between the contraction and relaxation

Resting Membrane Potential and Action Potential

• Resting membrane potential: At rest, nerve and muscle cells have an electrical potential difference across their membranes (negatively charge inside and positively charged outside the cell).

• Action potential (AP): A wave of depolarization that moves along the surface of the nerve or muscle cell membrane

• AP is due to the sudden change in the resting membrane potential (inside of the cell becomes positively charged)

• Caused by a sudden transient increase in permeability of the membrane to Na+ influx of Na+ into the cell from the ECF (extracellular fluid)

Neuromuscular Junction (Motor End Plate)

• Neuromuscular junction or motor end plate – the terminal branches of the axon of a motor neuron contacts the target muscle fibre

• No direct physical contact between the membranes of the nerve and muscle cells

• found near the middle of the muscle fibre

• Acetylcholine is stored in pre-synaptic vesicles

• An action potential initiates the release of 300 molecules of acetylcholine

• After crossing the gap, acetylcholine is broken down by acetylcholinesterase

Release of ACh and Na+

• when acetylcholine (ACh) is released during muscle contraction, sodium (Na+) ions are released into the muscle cell

• This influx of sodium ions is what initiates the process of muscle contraction

Excitation-Contraction (E-C) Coupling

• the process by which an electrical stimulus triggers the release of Ca2+ from the SR, initiating the mechanism of muscle contraction by sarcomere shortening

Process of EC

• (1) AP arrives at the neuromuscular junction and triggers ACh release, ACh diffuses across the synaptic cleft, binds to its receptors on the plasma membrane

• (2) the post-synaptic action potential propagates along the sarcolemma and down the T-tubules

• (3) triggers Ca2+ release from the SR

• (4) Ca2+ binds to troponin which undergoes a conformational change, removing the blocking action of tropomyosin

• Cross bridge cycle is triggered

• (5) contraction occurs

• (6) Ca2+ is actively removed and moved back into the SR when the action potential ends

• (7) tropomyosin blockage is restored, and the muscle relaxes.

Toxins associated with Junctionopathies

• Junctionopathies - Disorders of the Neuromuscular Junction

• Several proteins involved in synaptic transmission within the neuromuscular junction are the targets of naturally occurring or synthetic drugs

• Antagonists (inhibits or interferes) are shown as minus signs highlighted in red.

• Agonists (mimics) are shown as plus signs highlighted in green

• EXAMPLE: Botox - Botulinum Toxin

Muscle Cramps

• are involuntary and forcible uncontrollable muscle contractions that can’t relax

• can affect any muscle/ groups of muscles

• exercise associated muscle cramp (EAMC)

• nocturnal muscle cramps

In Vitro Muscle Contraction Experiments

Contractile behaviour of skeletal muscle (muscle twitch) is easily studied in vitro. Include:

• 1. Isometric Twitch (Contraction) of an Isolated Muscle

• 2. Summation and Tetanus

• 3. Concentric Twitch (Contraction) of an Isolated Muscle

Muscle Twitch

• simplest contract

• Shortening response to a single action potential or electrical stimulus (msec).

• Three phases (periods) of a muscle twitch:

  • 1. Latent Phase (2 msec) Membrane activation, Ca2+ release from SR, diffusion in interfilament space, deinhibition of actomyosin ATPase

  • 2. Contraction Phase

  • 3. Relaxation Phase

Summation

• If the muscle is stimulated before it fully relaxes, the force produced by the second twitch will be greater than the first

Incompleted Tetanus (Unfused tetanus)

• If we increase the frequency of stimulation the relaxation time between successive twitches will get shorter and shorter as the strength of contraction increases in amplitude. When there is still a partial relaxation

Complete tetanus (Fused tetanus)

• A stimulation frequency is eventually reached where there is no visible relaxation between successive twitches. The contraction becomes smooth and sustained

Fatigue

• Eventually the stimulated muscle will start to fatigue due to the multiple muscle twitches

Load (force) velocity curve

Load (force) power curve

Neurons

Afferent Neuron + Sensory Neuron:

• Receives information from a receptor

• Transmits information TOWARDS the CNS

Efferent Neuron + Motoneuron

• Transmits information AWAY from the CNS towards a muscle or gland

1. alpha (a) motor neuron - supply skeletal muscle fibres (muscle contraction)

2. gamma (g) motoneuron - supply muscle spindles (keep them taut)

Muscle Proprioceptors

• 1. Muscle spindle 2. Golgi tendon organ

  They determine the position of a limb in space from the following information:

• 1. joint angle 2. muscle length 3. muscle tension

Muscle Spindle

• Muscle spindles are connective tissue capsules (receptors) found in the perimysium (around fascicles)

• They contain specialized fibres (intrafusal) which have an afferent (impulses towards the CNS) and efferent (impulses away from the CNS) nerve supplies.

• Spindles monitor muscle movement

• γ (gamma) motorneurons cause contraction of spindle muscle fibres to bare the load during muscle contraction

Golgi Tendon Organ (GTO)

• GTOs are receptors

• Respond to tension rather than to length

• When forces of muscle contraction and/or external forces can cause injury to muscle, tendon or bone or when joints could be damaged during the shortening of muscles GTO sends stimulatory signals to activate the antagonist (opposite action muscle) and inhibitory signals for the agonist (same action muscle).

Reflex Arc

• the neural pathway that mediates a reflex action, which is a rapid, involuntary response to a stimulus