Lecture 7.2: Disorders of Muscle

Question 1

Myopathy

Answer 1

A primary disease of muscle

Question 2

Dystrophy

Answer 2

Degeneration of tissue due to disease (genetic)

Question 3

Atrophy

Answer 3

Wasting due to underuse

Question 4

Sarcopenia

Answer 4

Wasting as a result of ageing

Question 5

Hypertrophy

Answer 5

Increase in the size of an organ due to an increase in volume of its constituent
cells

Question 6

Hyperplasia

Answer 6

An enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferation

Question 7

Myosatellite Cells/ Satellite Cells

Answer 7

Aka muscle stem cells

Small multipotent cells with very little cytoplasm found in mature muscle

Question 8

Skeletal Muscle Repair

Answer 8

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)

Question 9

(Adult) Cardiac Muscle Repair

Answer 9

Is incapable of regeneration

Following damage, fibroblasts invade, divide, and lay down scar tissue

Question 10

Smooth Muscle Repair

Answer 10

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

Question 11

Remodelling of Skeletal Muscles

Answer 11

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

Question 12

Effect of Exercise on (Remodelling of ) Skeletal Muscles

Answer 12

Exercise also induces an increase in the number of mitochondria in skeletal muscle

Induces the release of myokines to exert systemic effects

Question 13

Adjustment of Muscle Length

Answer 13

Frequent stretching leads to the addition of sarcomeres and an increase in power

Inactivity leads to shortening

Question 14

Disuse Atrophy

Answer 14

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

Question 15

Sarcopenia

Answer 15

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

Question 16

When does skeletal muscle mass begin to decrease?

Answer 16

Skeletal muscle mass starts to decline from 30 years of age, with a 50% loss of by the age of 80

Question 17

What is atrophy accompanied by?

Answer 17

Atrophy is accompanied by an increase in connective tissue (including fat)

Question 18

Denervation Atrophy

Answer 18

Lower motor neuronlesions (i.e. damage occurring between the spinal cord and muscle) are associated with weakness, loss of tone (flaccidity) and muscle atrophy

Question 19

Neural Regeneration

Answer 19

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

Question 20

Ectopic Pacemaker

Answer 20

An excitable group of cells that causes a premature heart beat outside the normally functioning SA node of the heart

Question 21

Myasthenia gravis: What is it?

Answer 21

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

Question 22

Myasthenia gravis: Symptoms (4)

Answer 22

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).

Question 23

Myasthenia gravis: Management and Treatment

Answer 23

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

Question 24

Botulism

Answer 24

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

Question 25

Organophosphate Poisoning

Answer 25

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

Question 26

Types of Muscular Dystrophies

Answer 26

• Duchenne-type and Becker-type (‘Dystrophinopathies’) • Emery-Dreifuss • Limb Girdle • Facioscapulohumeral • Distal • Occulopharyngeal • Congenital

Question 27

Duchenne MD

Answer 27

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

Question 28

Progression of DMD

Answer 28

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

Question 29

Gower's Sign

Answer 29

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

Question 30

Muscle Fibre Damage in DMD

Answer 30

• 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

Question 31

Histological Changes in DMD

Answer 31

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

Question 32

Management/Treatment of DMD

Answer 32

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.

Question 33

Becker MD

Answer 33

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

Question 34

Limb Girdle MD

Answer 34

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

Question 35

Congenital MD

Answer 35

50% deficiency of the ECM protein merosin (laminin α-2) (a major component of the basement membrane)

Question 36

Emery-Dreifuss MD

Answer 36

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

Question 37

Facioscapulohumeral MD

Question 38

Distal MD

Question 39

Occulopharyngeal MD

Answer 39

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

Question 40

Inflammatory Myopathies

Answer 40

Diseases involving chronic muscle inflammation and weakness

Question 41

Polymyositis

Answer 41

• 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)

Question 42

Electrolyte Imbalances

Answer 42

Diuretic therapies that reduce blood pressure can lead to hypokalaemia (low K+) and muscle weakness Hypoparathyroidism leads to hypokalcaemia, which can cause muscle spasms

Question 43

Channelopathies: RYR-1-Related Diseases (What is it? Treatment?)

Answer 43

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

Question 44

Thyrotoxicosis

Answer 44

An excess of thyroid hormones can lead to protein catabolism and a loss of muscle mass (thyrotoxic myopathy)

Question 45

Rhabdomyolysis

Answer 45

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