Orlando Paciello » 5.Specific alterations to muscle fibres

Denervation

• Loss of any nerve impulse quickly results in atrophy of the muscle and, without innervation, practically half the muscle mass can be lost in the space of a few weeks.

• Generalized neuropathies or neuronopathies like equine motor neurone disease lead to widespread, symmetrical atrophy. Where there is damage to a particular nerve then asymmetrical atrophy is observed.

• One example is equine laryngeal hemiplegia secondary to a recurrent left laryngeal nerve lesion.

Img.2 Diagram illustrating denervation in muscle fibres. The fibres appear uniformly atrophied. Source: modified from Anderson J.R. Atlas pf Skeletal Muscle pathology MTP Press Limited

Neuropathic myopathies – morphology

Atrophic myofibres

Enervation leads to a particular type of atrophy, called pointed or angular (angular atrophy). In transverse section, the atrophic myofibres present in various bundles appear small and spiky with rounded corners (angular myofibres), which is because fibres near the atrophic ones become hypertrophic and so compress them.

Neuropathic myopathies – morphology (cont.)

Small group atrophy

Progression of preceding lesion whereby the number of atrophic angular myofibres increases and they tend to form small clusters.

Fiber-type Grouping

Denervated myofibres (A-C) can be reinnervated (D) by collateral nerves thus the fibres acquire the characteristics of the new motor unit (D).

Pyknotic Nuclear Clumps

If a denervated fibre is not reinnervated, atrophy continues with loss of myofibrils so that only the myonuclei remain in the sarcolemma.

This is the last stage in chronic denervation.

Big-group atrophy

When all the myofibres, or at least the majority, are enervated at the same time it gives rise to widespread, simultaneous atrophy, so the fibres do not assume their characteristic angular form but appear uniform and rounded in transverse section. In chronic states it is possible to find target fibres.

Target fibres

• Often observed in cases of acute denervation and reinnervation.

• Clearly seen with NADH stain. Characterized by a light or dark centre with a light halo round it and hyperactivity apparent in the area adjacent to the rest of the normal fibre.

Ragged Red Fibres

Vacuoles and aggregates of substances can be seen in many muscle pathologies. Vacuoles may contain lipids, glycogen or the products of degradation. Accumulation of abnormal mitochondria can be seen with Gomori’s trichrome.

Ragged-Red Fibres

- Mitochondrial myopathies

RRFs are typical of mitochondrial myopathies and are often associated with “Ragged Blue Fibers” which can be seen with SDH and with COX negative fibres
SDH and COX are both purely mitochondrial histoenzymatic stains.

RRFs and RBFs will be negative to the cytochrome oxidase stain (COX) when the abnormal proliferation of the mitochondria is associated with malfunctioning of these organelles.

Myopathy with enzymatic hole in the middle

This type presents with areas where enzyme activity is absent and are typical of Central Core Disease.

Splitting

This is a normal way for muscle fibres to divide but it can also occur in muscle pathologies like muscular dystrophy where the division is incomplete, along only part of the length of the fibre. Splitting is a process of regeneration and differentiation starting from a single fibre but it can also be a process of subdivision of hypertrophic myofibres.

Internal nuclei

The nuclei in a myofibre are normally located sub-sarcolemma. Migration towards the centre is a non-specific response.
Internal nuclei can be observed in myotonia and muscular dystrophy.

Increase in connective

Connective and adipose tissue substitute the muscle after necrosis.
In figure 1: Normal muscle. H.E.stain.

In figure 2: Serious increase in endomysial connective tissue in a case of muscular dystrophy (asterisk). H.E.stain

Segmental necrosis (Zenker degeneration)

• Histologically, myofibres in necrosis can have very different appearances. The earliest lesions show segmental hypercontraction, where segments are slightly larger in diameter and slightly darker in colour (A).
• The cytoplasm in really necrotic fibres is often homogeneously oesinophilic and pale-coloured (hyaline degeneration) with loss of cytoplasmic striations and adjacent nuclei.

• The increase in intra-cellular calcium is the common trigger for necrosis in all cells, and myofibres contain large amounts of calcium ions in the sarcoplasmic reticulum. This is why muscle fibres can be very sensitive to calcium-induced necrosis either when the sarcolemma is damaged leading to an influx of extra-cellular calcium, or when the sarcoplasm is damaged leading to the release of intra-cellular calcium deposits (B).

• Macrophages resulting from the transformation of monocytes in the blood quickly infiltrate the site of necrosis (sarcoclastosis [C]).

Regeneration by gemmation

After a few hours the sarcolemma nuclei start to multiply where the stumps are and appear surrounded by newly-formed sarcoplasma which emerges from each stump like a club-shaped bud. These grow into the young connective tissue which has continually filled the solution.

Immunohistochemistry

• Histochemical tests performed on non-fixed frozen sections of muscle represent the “gold standard” for muscle pathology.

• But we often turn to immunohistochemical tests for the study of cytoskeleton proteins, like dystrophyn and dystrophin-associated proteins.