Pathology of skeletal muscle

Question 1

What is muscular dystrophy?

Answer 1

A group of inherited disorders of muscle that begin in childhood, that lead to progressive weakness and muscle wasting. Muscle fibres undergo degeneration are are replaced with fibrofatty tissue and collagen.

Question 2

Define myopathy

Answer 2

disease of voluntary muscle

Question 3

Name four pathological processes that can affect muscle fibres

Answer 3

Acute inflammation and fibre necrosis

Inherited metabolic failure (genetic disease)

Hypertrophy and regeneration

Mitochondrial disease

Ion channel disorders

Question 4

What investigations could you do to determine if there has been muscle damage?

Answer 4

Blood test: serum creatine phosphokinase (CPK) is elevated in many dystrophies

Muscle biopsy: Histology of fibre types indicates denervation, inflammation and dystrophic changes. EM of muscle fibres for inflammation, necrosis or hypertrophy

Imaging: MRI

Question 5

Describe the 3 types of primary inflammatory myopathies

Answer 5

Polymyositis: Inflammatory myopathy of the proximal muscle. Facial weakness and dysphagia. No muscle pain. Inflammatory cells are found in the endomysium, necrotic and regenerating fibres are found throughout the fascicle.

Dermatomyositis is when the skin is involved, and there is a characteristic rash on the eyelids and fingers. Inflammatory infiltrates are found around the small blood vessels and there is atrophy and necrosis of fibres surrounding the fascicles.

Inclusion body myositis is where the distal muscles are involved e.g. quadriceps and flexors of the wrist and fingers. Inflammation causes formation of vacuoles in the myocytes.

Question 6

Describe the pathology of Duchenne muscular dystrophy

Answer 6

X-linked recessive disorder due to a mutation in the dystrophin gene (deletion/ frameshift mutations).

Dystrophin is essential for cell membrane stability. It forms a complex with laminin within the sarcolemma and cytoplasmic actin (interface between the intracellular contractile filaments and extracellular tissue matrix).

Dysfunctional protein causes myocyte weakness and degeneration. Fibres tear with repeated contractions.

Question 7

What is the histological appearance of muscle in DMD?

Answer 7

Variation in fibre size

Degeneration, necrosis and phagocytosis of muscle fibres

Regeneration of muscle fibres

Enlarged connective tissue in the endomysium

In later stages of the disease, the muscles become replaced by fat and connective tissue.

Question 8

What are the for pathalogical responses to injury in skeletal muscle?

Answer 8

Atrophy

Hypertrophy

Change in fibre type distribution

Necrosis/phagocytosis

Regeneration/fibrofatty replacement

Question 9

Describe the features of axonal degeneration

Answer 9

Result of primary destruction of the axon due to trauma or ischemia, with secondary disintegration of the myelin sheath.

The axon degenerates and Schwann cells begin to breakdown myelin and engulf axon fragments. Macrophages are recruited and remove axonal and myelin debris.

The proximal stumps of the degenerated axons sprout and elongate during the process of regeneration.

Question 10

What is the effect of degeneration/damage to nerves on muscle?

Answer 10

When nerve degeneration or damage occurs, the muscle fibres within the affected motor unit lose neural input.

Denervation leads to breakdown of actin and myosin, and decrease in cell size (denervation atrophy).

Question 11

What are the changes histological that occur in reinnervation of muscle?

Answer 11

Reinnervation of skeletal muscle changes its composition, because the distribution of type 1 and type 2 fibres is altered.

Fibre types are determined by the motor neuron innervating it. All muscle fibres in a single motor unit are the same type. In normal tissue fibres of a single motor unit are distributed alternately across the muscle. (checkerboard pattern with histochem)

Atrophic muscle fibres are reiinervated by the axons of unaffected neighbouring motor units sprouting in innervate the myocytes. Therefore the reinnervated fibres assume the properties of the neighbouring motor unit. (loss of checkerboard).

Question 12

When does type-specific atrophy occur in muscle?

(Type 2 - fast)

Answer 12

Type specific atrophy normally occurs in disease.

Type 2 fibre atrophy is common iwith inactivity or dissuse. This may occur following immobilisation of a fractured lumb, neurodegenerative diseases, or in therapy with glucocorticoids.

Question 13

What investigations could you carry out using a muscle biopsy sample?

Answer 13

H+E stain

Histochemistry

Immunochemistry

Electon microscopy

Biochemistry

Question 14

Compare the changes that occur in neurogenic disease vs. dystrophes and myopathies

Answer 14

Neurogenic disease:
Atrophy in groups of fibres
Compensatory hypertrophy
Fibretype grouping

Dystrophies and myopathies:
Hypertrophy and atrophy possible
Single fibre degeneration
Necrosis
Phagocytosis

Question 15

State 4 features of muscular dystrophies

Answer 15

Progressive

Genetically determined

Degenerative

Individual fibre loss

Regeneration/ Fibrosis

Result in abnormalities in contractile proteins and molecules connetinve muscle cells to the ECM

Question 16

What is myotonic dystrophy?

Answer 16

Sustained, involuntary contraction of a group of muscles.

Patiients complain of stiffness and have difficulty releasing their grip.

Can be elicited by percussion of the thenar eminence

Question 17

What is the clinical presentation of Duchenne Muscular dystrophy?

Answer 17

Difficulty running and rising to feet. Uses hands to climb up legs (Gower’s sign).

Proximal limb weakness.

Calf psudohypertrophy

CPK elevated