Lecture 7.2: Disorders of Muscle Flashcards
Myopathy
A primary disease of muscle
Dystrophy
Degeneration of tissue due to disease (genetic)
Atrophy
Wasting due to underuse
Sarcopenia
Wasting as a result of ageing
Hypertrophy
Increase in the size of an organ due to an increase in volume of its constituent
cells
Hyperplasia
An enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferation
Myosatellite Cells/ Satellite Cells
Aka muscle stem cells
Small multipotent cells with very little cytoplasm found in mature muscle
Skeletal Muscle Repair
Cells cannot divide, but can regenerate by mitotic activity of satellite cells, so that hyperplasia follows muscle injury
Satellite cells can also fuse with existing muscle cells to increase mass (skeletal muscle hypertrophy)
(Adult) Cardiac Muscle Repair
Is incapable of regeneration
Following damage, fibroblasts invade, divide, and lay down scar tissue
Smooth Muscle Repair
Retain their mitotic activity and can form new smooth muscle cells
This ability is particularly evident in the pregnant uterus where the muscle wall
becomes thicker by hypertrophy (swelling) and by hyperplasia (mitosis) of individual cells
Remodelling of Skeletal Muscles
Contractile proteins are replaced every two week
If destruction exceeds replacement then atrophy occurs
If replacement exceeds destruction then hypertrophy occurs, accompanied
by metabolic changes and an increase in blood flow
Effect of Exercise on (Remodelling of ) Skeletal Muscles
Exercise also induces an increase in the number of mitochondria in skeletal muscle
Induces the release of myokines to exert systemic effects
Adjustment of Muscle Length
Frequent stretching leads to the addition of sarcomeres and an increase in power
Inactivity leads to shortening
Disuse Atrophy
Seen in bed rest, limb immobilisation and sedentary behaviour
Affects extensor muscles more than flexor muscles
Loss of contractile proteins leads to reduced fibre diameter and a loss of power
Sarcopenia
Affects 5-10% of >65 year olds
Heat generated during muscle contraction is vital in maintaining body temperature
Risk of hypothermia increases with age
Sarcopenia can be effectively counteracted by resistance training
When does skeletal muscle mass begin to decrease?
Skeletal muscle mass starts to decline from 30 years of age, with a 50% loss of by the age of 80
What is atrophy accompanied by?
Atrophy is accompanied by an increase in connective tissue (including fat)
Denervation Atrophy
Lower motor neuronlesions (i.e. damage occurring between the spinal cord and muscle) are associated with weakness, loss of tone (flaccidity) and muscle atrophy
Neural Regeneration
If cell bodies remain intact, severed axons in the peripheral nervous system can undergo repair
This is supported by proliferating Schwann cells
Once neuromuscular junctions are re-established, muscle function is restored
Ectopic Pacemaker
An excitable group of cells that causes a premature heart beat outside the normally functioning SA node of the heart
Myasthenia gravis: What is it?
An autoimmune disease, associated with the destruction of the end-plate ACh receptors
Body creates Abs against post synaptic nicotinic receptors, this causes destruction as well as blockage. Means ACh cannot stimulate receptors and generate AP, leading to muscle weakness
This is accompanied by loss of junctional folds at the end-plate, and the widening of the synaptic cleft
Myasthenia gravis: Symptoms (4)
Facial weakness, drooping eyelids (ptosis) and double vision
Difficulty speaking, swallowing and breathing (in severe cases)
Fatigability and sudden falling due to reduced ACh signalling (limb weakness)
Severity of disease influenced by general state of health and emotion (e.g. tiredness and stress).
Myasthenia gravis: Management and Treatment
Avoiding anything that triggers the symptoms (tiredness/stress/medications)
Acetylcholinesterase (AChE) inhibitors, such as neostigmine and
physostigmine, increase ACh levels in the synaptic cleft
Surgery to remove the thymus gland
Botulism
Condition affecting neuromuscular transmission
Botulinum toxin (e.g. BoNT-A)
Released by the bacterium Clostridium botulinum blocks ACh release, leading to paralysis, e.g. of respiratory muscles
Organophosphate Poisoning
Condition affecting neuromuscular transmission
Organophosphate (OP) exposure is one of the most common causes of poisoning
Organophosphates inhibit acetylcholinesterase irreversibly, with wide ranging
neurotoxic effects
Death can result from respiratory failure or CVS problems
Sarin and Novichok are examples of organophosphates
Types of Muscular Dystrophies
• Duchenne-type and Becker-type (‘Dystrophinopathies’)
• Emery-Dreifuss
• Limb Girdle
• Facioscapulohumeral
• Distal
• Occulopharyngeal
• Congenital
Duchenne MD
X-linked recessive
Caused by mutations (mainly deletions) in the dystrophin gene
Results in loss of the actin-binding protein dystrophin (which normally links the cytoskeleton with the ECM and stabilises the sarcolemma)
Muscles without dystrophin are more sensitive to damage, resulting in progressive loss of muscle tissue and function, in addition to cardiomyopathy
Progression of DMD
Early onset (2-7 years), average age of diagnosis is at 4 years of age
Characteristic Gower’s Sign
Loss of independent ambulation at 13 years
Without intervention, the mean age at death is around 19 years
Affected individuals rarely live beyond their 20s, and normally die of respiratory failure as the disease progresses to head, chest and cardiac muscles
Gower’s Sign
A medical sign that indicates weakness of the proximal muscles, namely those of the lower limb
The sign describes a patient that has to use their hands and arms to “walk” up their own body from a squatting position due to lack of hip and thigh muscle strength
Muscle Fibre Damage in DMD
• Fragile sarcolemma tears during contraction
• Creatine (phospho)kinase liberated into serum
• Impaired calcium homeostasis damages contractile fibres
• Inflammation and necrosis
• Pseudohypertrophy occurs as fat and fibrous connective tissue replace
muscle fibres
Histological Changes in DMD
Muscle fibres stained for dystrophin showing membrane-associated expression (more opaque)
Trichrome staining showing increased adipose and connective tissue deposition, and atrophy of muscle fibres in DMD
Management/Treatment of DMD
Prenatal screening (in utero foetal muscle biopsy)
Corticosteroid therapy (prednisolone)
Future treatments: gene therapy with transfected myoblasts
Stop codon read-through agents and utrophin modulators (utrophin can act as a substitute for dystrophin)
Golodirsen & Viltepso are synthetic antisense oligonucleotides causing ‘exon skipping’ of abnormal exon 53 during the synthesis of the dystrophin gene, producing a shortened, but functional version of the dystrophin protein.
Becker MD
Deficiency in dystrophin function (rather than loss)
Dystrophin is necessary for the stability and protection of muscle
The gene mutation causes the dystrophin protein to be shorter than normal and not function normally
Limb Girdle MD
Deficiency of sarcoglycans (trans-membrane proteins important in ECM interactions)
These genes provide instructions for making proteins that are involved in muscle maintenance and repair
Congenital MD
50% deficiency of the ECM protein merosin (laminin α-2) (a major
component of the basement membrane)
Emery-Dreifuss MD
Caused by mutations in the EMD gene on the X chromosome that codes for the nuclear envelope protein emerin
Mutations occur throughout the gene and almost always result in complete absence of emerin from muscle or mislocalization of emerin
Loss of EDMD/emerin may result in deformation or breakage of nuclei of muscle cells
Thus reduction in muscle mass
Facioscapulohumeral MD
Distal MD
Occulopharyngeal MD
The problem is in a gene that has the information needed to make a protein called polyadenylate-binding protein (PABPN1)
The defect leads to a buildup of PABPN1 in the muscle cells
The PABPN1 clumps inside the muscle cells and may cause the cells to die
Causes weakness in the muscles around the upper eyelids and part of the throat called the pharynx
May affect vision and cause problems swallowing and talking
Inflammatory Myopathies
Diseases involving chronic muscle inflammation and weakness
Polymyositis
• It is an idiopathic inflammatory myopathy (IIM)
• Believed to have autoimmune or viral aetiology
• Proximal muscle weakness
• Chronic inflammation
• Necrosis of individual muscle fibres
• Frequently affects shoulder(s) and or hip(s)
Electrolyte Imbalances
Diuretic therapies that reduce blood pressure can lead to hypokalaemia (low K+) and muscle weakness
Hypoparathyroidism leads to hypokalcaemia, which can cause muscle spasms
Channelopathies: RYR-1-Related Diseases (What is it? Treatment?)
Makes you susceptible to severe reactions to certain general anaesthetics
Autosomal dominant mutation in the RYR1 gene, which encodes the subtype 1 ryanodine receptor (a Ca2+-release channel located in the SR)
Exposure to anaesthetics stimulates the release of stored Ca2+, leading to muscle contraction and the generation of excessive heat (Malignant hyperthermia-MH)
Treatment is with the RYR1 antagonist, and muscle relaxant dantrolene, and cooling
Thyrotoxicosis
An excess of thyroid hormones can lead to protein catabolism and a loss of
muscle mass (thyrotoxic myopathy)
Rhabdomyolysis
Rapid breakdown of skeletal muscle (e.g. following trauma, drug abuse or
excess exercise) results in leakage of muscle contents (e.g. myoglobin) into the circulation
Can cause kidney damage and ‘tea-coloured urine’
Can be fatal
Rhabdomyolysis is also a rare complication of statin use
