Muscle Physiology- Pt 2.docx

Motor Neuron Motor neurons are neurons whose cell body is located within the CNS (central nervous system: spinal cord and brain stem) and its’ axon travels within peripheral nerves and synapse with effector organs (such as muscle fibers). Skeletal muscles are controlled by motor neurons. Specificall...

Motor Neuron Motor neurons are neurons whose cell body is located within the CNS (central nervous system: spinal cord and brain stem) and its’ axon travels within peripheral nerves and synapse with effector organs (such as muscle fibers). Skeletal muscles are controlled by motor neurons. Specifically, each muscle fiber can only have one motor neuron attached. However, each motor neuron can be attached to multiple muscle fibers. For example, if a motor neuron is attached to multiple muscle fibers and has an action potential traveling down it, that action potential will stimulate all muscle fibers attached to the motor neuron. This demonstrates the “all or nothing” response associated with motor units. Neuromuscular Junction (NMJ) A neuromuscular junction is a specialized synapse formed from the attachment between the ending of a motor neuron and a muscle fiber. Given that a muscle fiber can only have 1 motor neuron attached to it, each muscle fiber can only have one neuromuscular junction. Electrical impulses (known as action potentials) can only travel unidirectionally across the neuromuscular junction. The NMJ is composed of a pre-synaptic side (AKA: pre-synaptic terminal), post-synaptic side/membrane (AKA: terminal plate), and a synaptic cleft. This composition is similar to most chemical synapses. Pre-synaptic Terminal The pre-synaptic terminal is the terminal portion of the motor neuron which has a button-like shape (sometimes referred to as the synaptic button). The pre-synaptic terminal contains a large portion of synaptic vesicles which is the storage chemical neurotransmitter known as acetylcholine. The pre-synaptic terminal also contains a large quantity of mitochondria due to the ATP and acetyl-Coa produced by the mitochondria having a useful role in the production and release of acetylcholine. The pre-synaptic terminal is localized at the inner surface of the termina; membrane and contains the “active zone” where specific proteins hold vesicles in the right place. Synaptic Cleft The synaptic cleft is the narrow space between the presynaptic and postsynaptic membranes. The synaptic cleft contains subneural clefts which consist of numerous small folds that increase the surface area of the muscle membrane. The synaptic cleft also consists of extracellular fluid and matric molecules that aid in neuron-muscle adhesion. Postsynaptic Membrane The postsynaptic membrane is located at the motor endplate. The postsynaptic membrane utilizes acetylcholine receptors and junctional folds to aid in synaptic transmission. Junctional folds consist of receptors at the mouth of the folds. These junctional folds align with the active zone of the presynaptic terminals. Motor Endplate The motor endplate is a modified junction of the muscle fiber membrane where a synapse occurs. A motor neuron axon terminal may have up to 50 motor units (synaptic knobs/boutons), however, each muscle fiber can only have 1 endplate. Motor Unit A motor unit consists of a motor neuron and all the muscle fibers that it innervates. Motor neurons vary in size. Small motor units control finer muscle movements, as they are attached to few muscle fibers. An example of a small motor unit would be extraocular muscles which typically have 1-4 muscle fibers attached to each motor neuron. Large motor units control more powerful movements, as they are attached to a higher quantity of muscle fibers. An example of a large motor unit would be quadricep muscles within 100-150 (or possibly more) muscle fibers attached to each motor neuron. The recruitment and gradation of force refers to the strength of a muscle contraction being controlled by the amount and frequency of motor unit activation, ultimately allowing for the adjustment of (contractile) force. Acetylcholine (ACh): General Info Acetylcholine is a chemical neurotransmitter of the neuromuscular junction released by nerve cells to send signals to other cells. Acetylcholine is synthesized from acetyl-coa and choline in the cytoplasm of the terminal. After being synthesized, acetylcholine is stored in vesicles and is lined up in rows within the active zone, until it is eventually released in the synaptic cleft. ACH refers to acetylcholine. ACHR refers to acetylcholine receptors. ACHE refers to acetylcholine enzyme (AKA: acetylcholinesterase). Acetylcholine: Release Steps Step 1: An action potential travels to the neuromuscular junction. Step 2: The action potential triggers the release of acetylcholine from vesicles within the terminal. Step 3: The release of acetylcholine triggers a wave of depolarization, thus opening the voltage gated calcium channels. Step 4: There is an influx of calcium into the presynaptic terminal. Step 5: The calcium influx triggers the activation of the synaptotagmin enzyme located in the vesicle membrane. Step 6: The activated synaptotagmin enzyme will activate the SNARE proteins. Step 7: the Snare Complex will then promote the docking, fusing, and release of acetylcholine via exocytosis. Acetylcholine: Action Acetylcholine will diffuse across the synaptic cleft to the postsynaptic membrane and bind to transmitter-specific receptors known as “nicotinic acetylcholine receptors”. The nicotinic acetylcholine receptors will also bind to nicotine. The nicotinic acetylcholine receptor is a ligand-gated ion channel which has 2 binding sites for acetylcholine (but does not require 2 acetylcholine to bind at once for activation). Acetylcholine binding to the nicotinic acetylcholine receptor, triggers the receptor to open allowing for: Localized depolarization of muscle fibers Influx of sodium into the cell Endplate potential increases in a positive direction (50-75millivolts) Muscle fibers can be depolarized by synaptic transmission. Acetylcholine: Degradation During acetylcholine degradation, acetylcholine is rapidly removed from the synaptic cleft within milliseconds of its release. The enzyme acetylcholinesterase destroys most of the acetylcholine by breaking it down into acetyl acid and choline. The choline is recycled by being transported back to the presynaptic terminal. Small amounts of acetylcholine will diffuse out of the cleft, causing it be no longer available for use. It is essential for acetylcholine to be degraded to prevent continuous re-excitation of muscle fibers. Organophosphate toxicosis Organophosphate toxicosis is a major cause of animal poisoning and is caused by insecticide, pesticide, and antiparasitic exposure at a toxic level. Exposure to small doses of insecticide, pesticides, and antiparasitics over a long period of time may not be harmful or have toxic impacts on animals. Organophosphate toxicosis causes the irreversible inactivation of acetylcholinesterase, preventing the degradation of acetylcholine. The irreversible inactivation of acetylcholinesterase results in an excess of acetylcholine and causes overstimulation of the acetylcholine receptors. Overstimulation of the nicotinic receptor causes: Muscle spasm and twitching (fasciculations) Overstimulation of the muscarinic receptors causes: Dyspnea (bronchoconstriction and increased bronchial secretions), diarrhea, vomiting, frequent urination, hypersalivation, colic, miosis (excessive eye constriction) Overstimulation of the central receptors causes: Nervousness, ataxia, seizures, hyperreactivity Prolonged overstimulation of these receptors can lead to desensitization of the receptors. Prolonged overstimulation happens in chronic cases of organophosphate toxicosis. In cases of desensitization, the muscle is no longer able to contract, resulting in flaccid paralysis. Similarly to Organophosphate Toxicosis, Carbamate will also inactivate acetylcholinesterase, however this inactivation is reversible. Carbamate toxicosis produces the same clinal signs as Organophosphate Toxicosis, however, the symptoms are present in shorter durations. Botulism Botulism is caused by the ingestion of Botulinum Toxin (neurotoxin). Clostridium botulinum is a gram positive, rod shaped, anaerobic bacteria that produces the botulinum toxin. Botulism can be contracted via the ingestion of contaminated uncooked or undercooked food. This food can be: decaying grass, decaying carcasses, hay, grains, or spoiled silage. The botulism toxin targets and destroys SNARE proteins via cleavage. The destruction of the SNARE proteins prevents the release of acetylcholine from the vesicles. Botulism has 7 types of toxins: A, B, C, D, E, F, G. Some species are more sensitive to one toxin type over another. Botulism is common within birds and chickens. Although botulism can occur in fish, horses, and cattle. Botulism can also occur in dogs and cats, although they are fairly resistant to all types of botulism toxins. Botulism commonly causes progressive motor paralysis and symptoms occur within hours to days after ingesting contaminated food. Other symptoms of botulism include: vomiting/regurgitation, dilated pupils, inability to blink, difficulty chewing or swallowing, atonic bladder, and constipation/ reduced peristalsis. An anti-toxin for botulism is an option for treatment. However, the anti-toxin must be given shortly after the ingestion of the contaminated food, as the anti-toxin will only work if the botulism toxin has NOT been activated yet. If the botulism toxin has already been activated and the anti-toxin is given to the patient, the patient will likely go into a state of anaphylaxis. Myasthenia Gravis Myasthenia Gravis is caused by the abnormal reduction of acetylcholine receptors on the neuromuscular endplate, resulting in the clinical sign of exercise-induced weakness. Myasthenia Gravis can be due to either the congenital form or the acquired form. Congenital form of Myasthenia Gravis The congenital form of Myasthenia Gravis is present from birth and results in recurrent and progressive muscle fatigue that becomes apparent at 6-9weeks of age. The congenital form of Myasthenia Gravis can be linked to problems with synthesizing acetylcholine receptors. Acquired form of Myasthenia Gravis The acquired form of Myasthenia Gravis is an autoimmune disorder where IgG is against acetylcholine receptors. Within the acquired from of Myasthenia Gravis, antibodies will do either of the following: Bind directly to the acetylcholine receptors, blocking the ion channels from opening. Increase the degradation of acetylcholine receptors within the postsynaptic membrane. The acquired form of Myasthenia Gravis can also cause complement-mediated lysis of the muscle endplate. Neuromuscular Transmission Problems: Key Points Organophosphate Toxicosis Organophosphate Toxicoses involves the irreversible inactivation of acetylcholinesterase, resulting in an excess of acetylcholine and overstimulation of the nicotinic receptors at the neuromuscular junction. Carbamate Carbamate involves the reversible inactivation of acetylcholinesterase. Botulism Botulism involves the destruction of SNARE proteins, preventing the release of acetylcholine. Myasthenia Gravis Myasthenia Gravis involves either insufficient production of acetylcholine receptors or immune-mediated acetylcholine receptor destruction.