What is the normal ratio of NMJs/muscle fibers in health people?
1 neuromuscular junction per muscle fiber
How are myonuclei arranged in muscles?
lots of nuclei per muscle fiber
What happens during alpha motor neuron
Initially before birth there are multiple alpha motor neurons per muscle fiber but this changes after birth due to pruning during development.
What happens if a terminal nerve cell dies and a neuromuscular junction is eliminated?
The dead cell can produce signalling molecules to create a replacement NMJ.
What is a motor unit?
A neuron and all the muscle fibers that it innervates. (each motor neuron innervates many muscle fibers)
What is the benefit of having more motor units per muscle fiber?
What is the benefit of having more myofibers per motor unit?
More power generation.
How do big muscles use motor units?
Big muscles can sequentially recruit Motor Units to increase force.
What happens to muscles if they are innervated by nerves that normally trigger another muscle fiber type? (i.e effect of cross-innervation)
The muscle will develop the properties of the nerve that innervates it.
What happens at neuromuscular junction?
Release of acetylcholine via exocytosis as a result of calcium binding to a protein on the acetylcholine containing vesicles.
Calcium enters the presynaptic cells via a voltage gated calcium channel.
Acetylcholine binds to nicotinic acetylcholine channels which opens up voltage gated sodium channels.
What happens when acetylcholine binds to nACHR?
It results in a sequence of events that lead to opening of the ion channel which is a part of this complex.
What happens if muscle cells are denervated?
No signal to the NMJ results in hyperactivity of AChR complex.
How are ryanodine receptors opened on SR?
They are activated by T-tubule dihydropyridine receptors.
How are muscle fiber types I, IIa, and IIb arranged in normal muscles vs neurogenic disease in muscles?
Normally muscle fiber types are random and many different muscle fiber types are located in close proximity to each other. However, when there is a disorder to motor neurons we can see fiber type clustering due to the branching of a single type of nerve.
What causes muscular dystrophies?
Damage and regeneration of muscle fibers as a result of multiple simultaneous innervations at different locations. (constant necrosis and repair)
What differentiates the physiology of fast and slow twitch innervating neurons?
The firing rate of these neurons.
What are the possible effects of muscle denervation?
Paralysis (happens immediately)
Fibrillation (Happens after days due to changes in muscle excitability)
Supersensitivity to ACh (happens after days due to increase in expression of AChRs)
Muscle atrophy (Denervation for longer than a week results in muscle protein loss)
Receptiveness to innervation (Muscle increases its ability to be innervated in response to denervation)
What is fasciculation?
Spontaneous firing of the injured nerve which results in twitch of motor units
How are neurogenic and myopathic diseases clinically similar?
Both cause weakness, muscle wasting, and loss of reflex activity.
What clinical symptoms are associated with neurogenic but not myopathic problems?
Fasciculations (twitchy fibers), sensory loss, hyperreflexia.
What lab signs are associated with myopathic but not neurogenic problems?
Reduced nerve conduction
Fiber type will be grouped on biopsy (due to innervation changes causing muscle fiber type switching.)
What lab signs are associated with myopathic but not neurogenic problems?
Lots of serum enzymes
Muscle biopsy will show necrosis and regeneration.
What are myasthenic disorders?
Disorders that affect acetylcholine release or binding to receptors in the NMJ.
What are the 2 most prevalent myasthenic disorders?
Lambert-Eaton Syndrome (affects voltage gated calcium channels)
Myasthenia Gravis (affects acetylcholine receptors)
What is myasthenia gravis?
Autoimmune disorder that affects transmission at the NMJ. Antibodies are produced against nicotinic ACh receptors. and so there is a reduced number of functional receptors.
What uscles are commonly affected by myasthenia gravis?
Cranial muscles + limb muscles with variable severity.
Does myasthenia gravis affect the muscle’s reflex ability and atrophy?
No it does not create the symptoms of denervation.
What is lambert-eaton syndrome?
Autoimmune disorder that affects transmission at the NMJ. Voltage gated Ca channels are blocked by autoantibodies resulting in a reduced amount of ACh release.
What conditions is Lambert-Eaton syndrome associated with?
Cancers (small cell lung cancer)
What muscles does lambert-eaton syndrome commonly affect?
Mainly proximal limb muscles but it can also affect respiratory muscles
How is the weakness associated with Lambert-Eaton syndrome usually treated?
Decreasing ACh breakdown via drugs like pyridostigmine.
Increasing calcium influx (3,4-diaminopyridine)
Can lambert-eaton syndrome cause inhibition of the ANS?
What is seen on histology slides of someone with muscular dystrophy?
Wide variation in size of myofibers
Fibrosis and fat infiltration
Hyper-contracted, split and whorled fibers
Internal nuclei and regenerating myofibers
What kind of condition is muscular dystrophy?
Spontaneous X-linked recessive condition present in 1/3500 of people.
What happens during muscular dystrophy?
Mutations in dystrophin gene. 30% of people with this condition get it due to a spontaneous mutation.
What are the symptoms of Duchenne’s Muscular Dystrophy?
Progressive muscle degeneration causing people to be wheelchair bound by age 10-12 years/
Death usually occurs by 20-30 years of age from cardiac arrest or respiratory failure.
What does dystrophin do?
Links the contractile apparatus to the plasma membrane and to the basal lamina (cell membrane).
Dystrophin damage causes the muscle cells to tear themselves apart.
What is Becker MDs?
A muscular dystrophy caused by damage to dystrophin that isn’t complete and allows muscle cells to continue functioning but at a compromised rate.
What is the difference between duchenne’s MD and Becker’s MD?
Duchenne’s MD is always fatal and caused by completely absent dystrophin. (due to out of frame transcript)
Becker’s MD is much less severe and results in altered size and amount of dystrophin. (partially to largely functional dystrophin)
What causes emery dreifuss muscular dystrophy (EDMD)?
Protein that links the muscles to the nucleus (protein is involved in nuclear lamina) is damaged. (this protein is found in most cells of the body)
What kind of cardiomyopathy is associated with EDMD?
What happens to myonuclei in EDMD?
They are destroyed by the force transduction.
What visible damage can be soon on histology slides in EDMD?
Lots of regeneration but not much necrosis
What gene mutations cause EDMD?
Mutations in EMD (emerin) [recessive] and LMNA (lamin) [dominant and this gene also causes hutchinson guilford progeria]
What is myotonia?
Problem with muscular contraction caused by an overactive chloride channel resulting in a long term holding of contraction longer than desired.(eg grip hard to release when initiated)
What mutation causes myotonia?
Altered ClCN1 gene resulting in altered ClC1 chloride channels on muscle fibers. This affects 1 in 100000 and is a highly variable phenotype.
What are the types of myotonia causing conditions>
Thomsen disease (autosomal dominant)
Becker disease (autosomal recessive)
What is motor neurone disease?
Progressive degeneration of CNS motor neurons affecting upper and lower motor MNs.
What is the risk of motor neurone disease?
1:300 people diagnosed and most people get it after 50 years.
How long do people usually survive with motor neurone disease?
Within 3 years and no known cure exists and treatments are limited.
What causes motor neurone disease?
Unknown but 1 cause of this disease is SOD mutations.
What are the subtypes of motor neurone disease and which neurones are affected by this condition?
Amyotrophic lateral sclerosis (UMNs + LMNs)
Progressive bulbar palsy (LMNs and CN 9 - 12)
Progressive muscular atrophy (LMNs)
Primary lateral sclerosis (UMNs)
What is the difference seen between motor neurone disease caused by LMNs and UMNs?
LMN: Weakness, fasciculation, muscular atrophy from muscle denervation.
UMN: Hyperreflexia and spasticity result from degeneration of the lateral corticospinal tracts in the spinal cord
How does polio cause its symptoms?
Viral invasion of motor neurons results in inflammation and damage/destruction of motor neurons resulting in paralysis, pain, loss of reflexes and weakness.
What happens during recovery from polio?
Due to damaged nerves stopping their innervation of some motor units, the already present axons start to grow and innervate those axons resulting in more uniformity of muscle fiber types and size of the motor units.
What is post-polio syndrome?
A condition present in 20 - 25% of the people that recover from polio.
The dexterity of muscles is lost and fatigue + weakness happens.