Nerve and Muscle

DR/ MOHAMED HASSAN doctorpioneer@yahoo.com

The Nervous System

Dont get nervous about the nervous system

 Nerve and Muscle

Nerve and muscle are excitable cells i.e. able to respond to a stimulus by changing the electrical properties of their cell membranes.

 Neuron- basic structural unit of the nervous system Dendrites- carry impulses towards the cell Axon-carry impulses away from the cell Myelin sheath Synaptic terminal
Epinephrine Norepinephrine Acetylcholine

Structure of the neuron:

Cell body: It contains a nucleus, cytoplasm, mitochondria, lysosomes, endoplasmic reticulum and Golgi complex. Dendrites: They are multiple, short and thick extensions of the cytoplasm of the cell body. Their function is to receive signals from other nerve cells and conduct them toward the cell body.

 Axon (= nerve fiber) conducts impulses away from the cell body towards its terminals. Axons may be covered with a whitish, fatty segmented sheath called myelin sheath. The gaps in the myelin sheath are called nodes of Renvier. Myelin sheath protects and electrically insulates fibers from one another. Also, it increases the speed of transmission of nerve impulse.

 Properties of Nerves: 1-Excitability: It is the ability of the nerve to respond to adequate stimulation. 2-Conductivity: It is the ability of the nerve to respond by conducting the nerve impulses. 3-Infatiguability: nerve fibers are not fatigued by repeated stimulation.

Resting Membrane Potential (RMP)

Definition: It is the potential difference between the outer surface and the inner surface of the membrane of excitable tissues (nerve & muscle) under resting condition. The inside of the membrane is negatively charged with respect to the outside.

Causes of the resting membrane potential:

(I) Passive Forces (93%) = Selective

A] Permeability of the membrane to potassium (K+) ions is 50-70 times more than its permeability to sodium (Na+) ions at rest. At rest, K+ ion concentration is high inside the membrane than outside and the concentration of Na+ ions is the opposite. Leakage membrane channels allow K+ to diffuse outward and Na+ to diffuse inward across the cell membrane. However, the cell membrane is more permeable to K+ than to Na+ so, + ve ions are lost from inside.

Permeability Of The Membrane:

 B] The membrane is not permeable to the negatively charged proteins, organic phosphate and sulfate ions. So, negatively charged molecules are retained inside.

 (II) Active force (7 %) = Na+- K+

Na+ - K+ pump acts during rest to share in building and stabilizing RMP by pumping 3 Na+ to the outside and 2 K+ to the inside It is electrogenic pump that requires energy provided from ATP by the activity of Na+ - K+ ATPase enzyme.

Pump.

Action Potential
Definition: It is the change in the membrane potential of an excitable cell (nerve or muscle) in response to stimulation by threshold stimulus.

Phases of Action Potential and Its Ionic Basis:

Latent period: Isopotential interval represents the time needed by the stimulus to travel along the axon to reach the recording electrode. Depolarization phase: At the beginning of action potential, the depolarization is slow and when the membrane potential reaches (-55 mv) the firing level is reached, the rate of depolarization increases markedly and the membrane potential overshoots beyond the zero level and become (+35 mv). Reversal of polarity occurs = inner surface of the membrane becomes positive in relation to outside. The magnitude of action potential=105 mv.

 Repolarization phase: At the end of depolarization, the membrane potential returns back to the resting level. After 70% of repolarization, the rate of repolarization becomes more slow (=after depolarization). Then, the membrane potential become more negative (-ve) than original resting membrane potential (=after hyperpolarization) Finally, the resting membrane potential (RMP) is restored.

Neuromuscular Transmission

 The action potential in a motor neuron is rapidly propagated from the central nervous system (CNS) to the skeletal muscle along the large myelinated fiber (axon) of the neuron. As the axon approaches a muscle, it divides into many terminal branches and loses its myelin sheath. Each of these axon terminals forms a neuromuscular junction. The axon terminal is enlarged into a knob like structure (the terminal button), which fits into a shallow depression or groove in the underlying muscle fiber

Mechanism of Neuromuscular Transmission:

Transmission of impulses from the motor nerve to the muscle is carried out chemically by acetyl choline. It include 3 steps: - Release of acetyl choline. - Depolarization of the MEP. - Destruction of acetyl choline.

 Release of acetyl choline:

When nerve impulse ( action potential ) reaches the axon terminal of a motor neuron causes opening of voltage-gated Ca2+ channels Ca2+ diffuses to the interior of the axon terminal release of acetyl choline (from the vesicles by exocytosis) into the synaptic space.

 Depolarization of motor end plate: The released acetyl choline binds to acetyl choline receptor sites, present on the motor end plate, causes opening of ligand-gated Na+ channels depolarization of the motor end plate, which is local potential, known as the end plate potential ( EPP ). In turn, this end plate potential initiates an action potential at the muscle membrane which become conducted along the muscle fiber initiates muscle contraction.

 Destruction of acetyl choline: - After performing its action, acetyl choline is then removed from the synaptic cleft by acetyl cholinesterase enzyme, which is present in high concentration at the neuromuscular junction. - Removal of acetyl choline terminates EPP, thus, no more action potentials are initiated in the muscle fiber.

 Drugs & chemicals that affect transmission at the neuromuscular junction:

Inhibit transmission at the neuromuscular

junction:

A- Block acetyl choline receptor sites: e.g. Curare: - competes with acetyl choline for the acetyl choline receptor sites. - Large dose of curare death from respiratory paralysis caused by an inability to contact the diaphragm. * D-tubocurarine is used clinically in suitable doses as muscle relaxant; to produce muscle relaxation during surgical operation

 B- Block release of acetyl choline: e.g. Botulinum toxin: - is a bacterial toxin, responsible for canned food poisoning. - decreases the release of acetyl choline by the nerve terminals. - is one of the most lethal poisons known: death is due to respiratory failure caused by the inability to contract the diaphragm.

 Stimulate transmission at the

neuromuscular junction:

A- Acetyl choline like action: e.g. - metacholine, carbachol and nicotine in small dose(have the same effect on the muscle fiber as does the acetyl choline),

 B- Prevents inactivation of acetyl choline: ( by inhibiting acetyl cholinesterase )

inactivate acetyl cholinesterase for several hours, after which acetyl cholinesterase becomes active again. Organophosphates (long- acting): e.g. some pesticides and military nerve gases inactivate acetyl cholinesterase for weeks death.
Neostigmine & physostigmine (short -acting):

 Myasthenia Gravis: ( myasthenia = muscle weakness, gravis = severe ). - is a disease characterized by extreme muscle weakness because neuromuscular junction is unable to transmit signals from the nerve fiber to the muscle fiber. Cause: It is autoimmune disease of unknown cause; in which the body produces antibodies against its own motor end plate acetyl choline receptors the antibodies destroy some of the acetyl choline receptors EPP formed is too week to adequately stimulate the muscle fiber.

Treatment: By short-term anticholinesterase drug e.g.,Neostigmine: It temporarily inhibits acetyl cholinesterase accumulation of acetyl choline in the synaptic cleft prolongation of the action of cetyl choline at the neuromuscular junction EPP of sufficient magnitude to initiate action potential and subsequently contraction in the muscle fiber.

 Muscle Action Potential: It is like action potential in nerve fiber, except for quantitative differences: Resting membrane potential is about 80 to 90 mV in skeletal muscle fiber. Duration of action potential in skeletal muscle is 5 times longer than that of large myelinated nerve. 3- Velocity of conduction of action potential in skeletal muscle is slower than that in myelinated nerve.

 Types of Muscle
There are three general types of muscle

tissues:

Skeletal muscle responsible for movement. Cardiac muscle responsible for pumping blood. Smooth muscle responsible for sustained contractions in the blood vessels, gastrointestinal tract and other areas in the body.

 Structure of Skeletal Muscle: -Skeletal muscle consists of a number of muscle fibers lying parallel to each other & bundled together by connective tissue and attached to bones by tendons. The fibers extend the entire length of the muscle.

 A single skeletal muscle cell ( known as muscle fiber ):is large, elongated & cylindershaped, contains multiple nuclei, contains many mitochondria (generate energy), contains numerous
- Each myofibril consists of a regular arrangement of:

myofibrils.

thick filaments: made up of the protein myosin. thin filaments: made up primarily of the protein actin.

 A band: a-the myosin filaments (thick filaments). b-the ends of the actin filaments where they overlap the myosin. H zone: - is lighter area in the middle of A band. - contains only the central parts of the myosin filaments

 I band: - contains only actin filaments(thin filaments). Z line: - extends vertically in the middle of each I band. - Is a flattened disc-like protein. - Connects the thin filaments of 2 adjoining sarcomeres.

 Sarcomere: - is the area between 2 Z lines. - is the functional unit of skeletal muscle. i.e., the smallest part of a muscle fiber that is capable of contraction. - consists of one whole A band & of each of the 2 I bands located on either side.

 Thick filaments: - Each myosin molecule is a protein consisting of 2 identical subunits, with their tails coiled around each other and their 2 heads projecting out at one end. - These heads form the cross bridges between the thick & thin filaments.

 Thin filaments: are composed of 3 proteins: Actin molecules : (is the main protein ) Each actin molecule has cross bridge binding site, for attachment with a myosin cross bridge.

 Tropomyosin molecules - are thread like proteins that lie alongside the actin spiral. - cover the cross-bridge binding sites present on actin prevent the integration between actin & myosin Prevent muscle contraction.

 Troponin molecules: - are small globular molecules located at intervals along the tropomyosin molecules. - Each molecule is formed of 3 polypeptide units: Troponin T: binds to tropomyosin Troponin I: binds to actin Troponin C: binds with Ca2+

 Binding of Ca2+ to troponin C: When Ca2+ binds to troponin C change troponin shape pull troponin-tropomyosin complex away from actin uncover (expose) cross bridge binds sites on actin myosin cross bridges bind to actin contraction of muscle fiber.

 Contractile proteins: are actin & myosin. Regulatory proteins: Are troponin & tropomyosin: - They cover the cross bridge binding sites muscle relaxation. - With Ca2+, they expose crossbridge binding sites muscle contraction.

 Function of T tubules: Because the T tubule membrane is continuous with the surface membrane, it rapidly transmits action potential from the surface membrane into central portions of the muscle fiber.

 Action potential in the T tubule causes rapid opening of the Ca2+ channels in the sarcoplasmic reticulum release of Ca2+ into the sarcoplasm surrounding the myofibrils the released Ca2+ binds with troponin C muscle contraction

 Sarcoplasmic Reticulum (S.R.): - is a fine network of interconnected tubules surrounding each myofibril. - runs longitudinal down the myofibril, but is not continuous: -the ends of each segment expand to form the lateral sacs (terminal cisterns ), which lie adjacent to the T tubules.

 Molecular Basis of Skeletal Muscle Contraction:

Excitation of skeletal muscle fiber by its motor neuron, causes muscle contraction. Sliding filament mechanism of muscle contraction: - The thin filaments on each side of a sarcomere slide inward toward the center of the thick filaments during contraction. - As they slide inward, the thin filaments pull the Z lines to which they are attached closer together, so the sarcomere shortens.

 Excitation-Contraction Coupling: It is the process by which an action potential of muscle fiber initiates muscle fiber contraction:
Action potential in the neuron terminal release of acetyl choline action potential in the muscle fiber membrane, that spreads down into the T tubules release Ca2+ from the lateral sacs of S.R.

 released Ca2+ binds to troponin C, changing its shape pulling troponinTropomyosin complex away from actin uncovering (exposing) cross bridge binding sites, present on actin

 actin binds to myosin cross bridges, which have previously been energized ( by the splitting of ATP into ADP + Pi + energy, by the myosin ATPase site on the cross bridge ).

 3- Binding of actin with the energized myosin cross bridges release the energy stored within the cross bridges the cross bridge binds inward, producing a power stroke that pulls the thin filaments inward. Inward sliding of all the thin filaments surrounding a thick filaments shortens the sarcomere ( i.e., muscle contraction ).

 4- During a power stroke ADP & Pi (inorganic phosphate) are rapidly released from myosin, this frees myosin ATPase site for attachment of another ATP molecule.

 5- Attachment of a new ATP molecule permits detachment of the cross bridge from actin. 6- The cross bridge returns to its original shape & becomes ready to start another cycle: the newly attached ATP is then split by myosin ATPase energizing the cross bridge once again, the energized cross bridge binds to the next actin molecule, and repeats the cycle.

 7- Repeated cycles of cross bridge activity slide the thin filaments inward step-by-step complete shortening of the muscle fiber.

 Muscle relaxation: 1- when the muscle action potential ceases no longer action potential in the T tubules no release of Ca2+.

 The Ca2+ -pump of the S.R. actively returns the released Ca2+ back into the sarcoplasmic tubules. 3- Removal of Ca2+ troponin-tropomyosin complex returns to its blocking position cover the cross bridge binding sites present on actin myosin can not bind to actin. 4- The thin filaments return to their resting position muscle relaxation.

The actin and myosin remain linked together at the cross-bridge until a fresh molecule of ATP attaches to myosin, allowing the link between actin and myosin to be broken at the end of a cycle. Pumping of Ca2+ back into S.R. by Ca2+ - ATPase pump is energy comsuming i.e., is active process.

 Fatigue When a muscle is maintained contracting for a long time, its force of contraction decreases. This is called fatigue.

 Types of fatigue: A) Muscle fatigue: Accumulation of lactic acid acidosis, which inhibits the enzymes necessary for energy-producing pathways and excitation contraction coupling process. Depletion of energy reserves (i.e., muscle glycogen is consumed).

 B) Neuromuscular fatigue: Prolonged muscle activity depletion of acetylcholine stored in the terminal button vesicles transmission of the action potential from the motor neurons to the muscles

 C) Central (psychological) fatigue: - Lack of strong motivation (a will to win). - Lack of sleep. - Discomfort.