Myopathic Changes

Slide 1 · MYOPATHIC CHANGES

Morphology • injury–repair • diagnostic interpretation

Skeletal muscle pathology

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how focal myofiber necrosis initiates macrophage clearance and satellite-cell repair.

Recognize regeneration, chronic fiber loss, fibrosis, fatty replacement, and abnormal inclusions.

Distinguish selected myopathic patterns from denervation and identify illustrative etiologies.

Slide 3 · The scope of a myopathic pattern

Intrinsic myofiber injury

Segmental necrosis

Regeneration

Fibrosis / fat in chronic injury

Loss of innervation

Motor-unit dropout

Grouped angular atrophy

Fiber-type grouping

Slide 4 · A myofiber is a multinucleated cell

Myoblast fusion produces elongated multinucleated myotubes and mature myofibers.

Myofibers contain organized contractile sarcomeres along their length.

One fiber can undergo damage in only part of its length.

Segment of a multinucleated myofiber

Ordered sarcomeres

Schematic — not a clinical or histologic specimen

Slide 5 · Fascicles organize myofibers

Individual myofibers are grouped in fascicles.

The endomysium surrounds individual fibers; Connective tissue also separates fascicles.

This arrangement makes fiber loss, fibrosis, and perifascicular patterns recognizable.

Arrangement within a muscle fascicle

Schematic — not a clinical or histologic specimen

Slide 6 · Satellite cells support repair

Small tissue stem-cell populations reside in adult skeletal muscle.

After injury, activated satellite cells provide a cellular source for regeneration.

Regeneration depends on the remaining tissue framework and continued injury burden.

Cellular repair at the myofiber surface

Satellite cell

A reserve for injury-induced regeneration

Schematic — not a clinical or histologic specimen

Slide 7 · Fiber types serve distinct functions

Type I fibers: Sustained force, high oxidative capacity, high fatigue resistance.

Type II fibers: Rapid movement, greater power, greater glycolytic capacity.

Relative fiber proportions and atrophy patterns carry diagnostic information.

Type I / type II muscle fibers

Type I

Oxidative • sustained force

Type II

Glycolytic • rapid force

Schematic — not a clinical or histologic specimen

Slide 8 · Histochemical fiber typing

NADH-TR activity is darker in type I fibers and lighter in type II.

ATPase at pH 9.4 shows the opposite contrast: Type I light, type II dark.

Stain and assay conditions must be known before interpreting color.

Type I / type II muscle fibers

Type I

Oxidative • sustained force

Type II

Glycolytic • rapid force

NADH-TR: I darker | ATPase pH 9.4: II darker

Schematic — not a clinical or histologic specimen

Slide 9 · Normal fibers form a checkerboard

Type I and type II fibers are admixed throughout healthy muscle.

Opposite-type fibers appear intermingled rather than clustered into large uniform groups.

Marked fiber-type grouping is instead a clue to previous denervation and reinnervation.

Fiber-type distribution

Type I

Type II

Schematic — not a clinical or histologic specimen

Slide 10 · Muscle atrophy is not disease-specific

Reduced myofiber size occurs after loss of innervation, disuse, aging, cachexia, and myopathy.

The spatial distribution of small fibers is more informative than atrophy alone.

Interpret muscle atrophy together with other injury and repair features.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 11 · Three informative patterns of atrophy

Morphologic finding

Interpretation

Grouped small fibers

Denervation / neurogenic

Perifascicular small fibers

Dermatomyositis

Type II selective atrophy

Corticosteroids / disuse

Slide 12 · Myopathic versus neurogenic injury

Myopathic mechanism

Direct injury

Muscle enzyme release

Repair may restore sarcomeres

Neurogenic mechanism

Loss of trophic input

Angulated grouped atrophy

Reinnervation reorganizes fiber type

Slide 13 · Primary myopathy: The morphologic vocabulary

Morphologic finding

Interpretation

Segmental fiber necrosis

Damage

Basophilia + prominent nuclei

Repair

Endomysial collagen / fat

Chronic remodeling

Vacuoles / aggregates

Selected structural disorders

Slide 14 · Segmental necrosis spares part of the fiber

A myofiber is long and tube-like; Injury can be confined to a short segment.

Degeneration disrupts sarcomeres and other structures within the injured region.

Surviving portions of the same fiber can participate in restoration.

Segment of a multinucleated myofiber

Local segment disrupted; Remainder persists

Schematic — not a clinical or histologic specimen

Slide 15 · Injury–repair sequence

Segmental damage

Debris clearance

Satellite-cell fusion

Sarcomere restoration

Conceptual sequence — no numeric timing or quantitative scale

Slide 16 · Creatine kinase reflects myofiber damage

Myofiber injury

Cytoplasmic CK release

Increased serum CK

Interpret with clinicopathology

Conceptual sequence — no numeric timing or quantitative scale

Slide 17 · CK: Injury signal, not a diagnosis

What CK helps establish

Muscle injury is occurring

Supports destructive fiber injury

Can guide further evaluation

What CK cannot establish

Specific immune vs toxic etiology

The histologic distribution

The presence of a particular inclusion

Slide 18 · Macrophages clear a necrotic segment

Macrophages engulf damaged sarcomeres and other necrotic fiber contents.

This removal process is termed myophagocytosis.

The fiber’s connective-tissue context helps orient the repair sequence.

Segment of a multinucleated myofiber

Macrophages remove damaged contractile material

Schematic — not a clinical or histologic specimen

Slide 19 · Myophagocytosis precedes regeneration

Necrotic sarcomeres

Macrophage engulfment

Clearance of debris

Rebuilding becomes possible

Conceptual sequence — no numeric timing or quantitative scale

Slide 20 · Satellite-cell fusion repairs the fiber

After activation, satellite-cell progeny fuse with damaged myofibers.

The resulting regenerated portion gains the capacity to produce new sarcomeres.

Repair is a cellular rebuilding process, not simple scar formation.

Cellular repair at the myofiber surface

Satellite cell

Activation → fusion → repair

Schematic — not a clinical or histologic specimen

Slide 21 · New sarcomeres restore contractile continuity

Replacement of lost contractile elements follows removal of necrotic material.

In favorable acute injury, the original fiber becomes structurally continuous again.

Repeated injury may outpace this restorative process.

Segment of a multinucleated myofiber

New sarcomeres span the repaired segment

Schematic — not a clinical or histologic specimen

Slide 22 · Recognizing a regenerating fiber

Regenerating myofibers are rich in RNA.

In hematoxylin and eosin sections, this RNA-rich cytoplasm appears basophilic.

Regeneration can be recognized alongside degenerating fibers in an active lesion.

Simplified cross-sectional pattern

Blue-gray fibers designate RNA-rich regeneration

Schematic — not a clinical or histologic specimen

Slide 23 · Regenerating nuclei are conspicuous

Regenerating fibers contain enlarged nuclei with prominent nucleoli.

Nuclei may lie at varied positions within the cytoplasm.

This contrasts with the usual subsarcolemmal placement of mature myofiber nuclei.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 24 · Basophilia and internal nuclei: Interpretation

Mature myofiber

Relatively peripheral nuclei

Established contractile apparatus

Not strongly basophilic

Regenerating myofiber

RNA-rich basophilic cytoplasm

Large nucleolated nuclei

Nuclei may be internal

Slide 25 · Acute injury can heal structurally

Transient insult

Localized degeneration

Effective regeneration

Restored fiber continuity

Conceptual sequence — no numeric timing or quantitative scale

Slide 26 · Chronic injury exceeds repair capacity

Persistent insult

Repeated fiber injury

Regeneration falls behind

Dropout + replacement

Conceptual sequence — no numeric timing or quantitative scale

Slide 27 · Myofiber dropout reduces contractile mass

Dropout refers to loss of fibers that are not replaced by successful regeneration.

The resulting deficit contributes to chronic muscle weakness.

Dropout is often accompanied by increased interstitial connective tissue.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 28 · Endomysial fibrosis replaces lost fibers

Fibrosis is deposition of collagen in the endomysial compartment.

It is a prominent marker of chronic, incompletely repaired muscle injury.

Fibrosis separates residual fibers rather than recreating contractile elements.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 29 · Fatty replacement marks chronic remodeling

Adipose tissue can occupy regions of lost skeletal muscle.

Fibrosis and fatty replacement frequently coexist in long-standing disease.

They reflect tissue remodeling, not active fiber regeneration.

Simplified cross-sectional pattern

Yellow cells represent fatty replacement

Schematic — not a clinical or histologic specimen

Slide 30 · A chronic injury trajectory

Cycles of injury

Failed replacement

Fiber loss

Fibrosis + fatty change

Conceptual sequence — no numeric timing or quantitative scale

Slide 31 · Atrophic fibers may coexist with regeneration

The nature of the primary insult determines whether atrophic fibers are also present.

A single biopsy may show injury, repair, and chronic remodeling concurrently.

Do not infer uniform timing for all fibers in a diseased muscle.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 32 · Hypertrophy is not always pathologic

Physiologic activity can enlarge muscle fibers.

Some chronic myopathies also feature fiber hypertrophy.

An enlarged fiber has meaning only in its tissue and clinical context.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 33 · Chronic myopathy can show compensatory enlargement

Physiologic enlargement

Exercise-linked adaptation

Not sufficient for diagnosis

Evaluate normal surrounding muscle

Chronic myopathy

May contain enlarged survivors

Can coexist with fiber dropout

Interpret with necrosis and repair

Slide 34 · Inclusions point toward specific mechanisms

Morphologic finding

Interpretation

Vacuolar change

Lysosomal / inclusion body examples

Protein aggregates

Sporadic inclusion body myositis

Clustered organelles

Specific primary myopathies

Slide 35 · Vacuoles are a structural finding

A vacuole appears as an altered or empty-appearing region within myofiber cytoplasm.

Certain drug-associated and inclusion body myopathies produce vacuolar changes.

Vacuoles require context: Different pathogenic pathways can yield similar spaces.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 36 · Protein aggregates change the differential

Some myopathies accumulate abnormal cytoplasmic proteins.

Inclusion body myositis combines rimmed vacuoles with abnormal protein aggregates.

The source describes β-amyloid, TDP-43, and ubiquitin among these aggregates.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 37 · Clustered organelles can be pathologic

Abnormal distributions of cellular organelles are an inclusion category.

Mitochondrial and lysosomal disorders provide mechanistic examples.

The precise ultrastructural lesion matters more than merely noting an inclusion.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 38 · Do not equate every vacuole with necrosis

Inclusion or vacuolar pattern

Vacuolated cytoplasm

Storage / lysosomal pathway clues

May not indicate active necrosis

Destructive injury pattern

Segmental degeneration

Macrophage myophagocytosis

Can raise serum CK

Slide 39 · Neurogenic atrophy starts with denervation

Loss of a motor axon deprives its fibers of trophic input.

Affected fibers become smaller and often angulated.

Groups of similarly affected fibers can arise because motor units are lost together.

Motor neuron and dependent fibers

MN

One motor unit

Schematic — not a clinical or histologic specimen

Slide 40 · Grouped angulated fibers favor denervation

Clustered small, flattened, angulated fibers are a classic neurogenic pattern.

Group atrophy differs from isolated or scattered fiber shrinkage.

This comparison prevents an overdiagnosis of primary myopathy.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 41 · Reinnervation reorganizes motor units

Surviving axons may capture formerly denervated myofibers.

Motor-unit size increases and reinnervated fibers may adopt a different fiber type.

The resulting distribution becomes less checkerboard-like.

Motor neuron and dependent fibers

MN

One motor unit

Schematic — not a clinical or histologic specimen

Slide 42 · Fiber-type grouping records reinnervation

One motor neuron innervates fibers of a single functional type.

Reinnervation can produce large adjacent regions of one fiber type.

Ongoing denervation of the expanded unit may produce subsequent grouped atrophy.

Fiber-type distribution

Type I

Type II

Schematic — not a clinical or histologic specimen

Slide 43 · A paired comparison of biopsy patterns

Myopathic pattern

Necrosis and regeneration

Hypertrophy / atrophy

Some distinctive inclusions

Neurogenic pattern

Grouped angular atrophy

Reinnervation / type grouping

Motor-unit dependence

Slide 44 · Type II atrophy illustrates another mechanism

Prolonged corticosteroid treatment can preferentially reduce type II fiber size.

Disuse may yield a similar selective pattern.

Selective atrophy differs from the segmental necrosis–regeneration sequence.

Type I / type II muscle fibers

Type I

Oxidative • sustained force

Type II

Glycolytic • rapid force

Corticosteroids / disuse → type II fiber atrophy

Schematic — not a clinical or histologic specimen

Slide 45 · Distribution can suggest dermatomyositis

Perifascicular atrophy refers to preferentially small fibers at fascicle margins.

The pattern is a recognized lesion in dermatomyositis.

It is not present in every case and should be integrated with other findings.

Arrangement within a muscle fascicle

Small fibers near fascicle edge

Schematic — not a clinical or histologic specimen

Slide 46 · Perifascicular injury: Why location matters

In dermatomyositis, vascular and interferon-associated abnormalities accompany muscle injury.

Perifascicular atrophy highlights the arrangement of damage within the fascicle.

The source emphasizes that mechanisms remain incompletely established.

Arrangement within a muscle fascicle

Small fibers near fascicle edge

Schematic — not a clinical or histologic specimen

Slide 47 · Necrosis may dominate despite sparse inflammation

Immune-mediated necrotizing myopathy features extensive fiber necrosis and regeneration.

Inflammatory infiltrates are often relatively scant.

The presence of myonecrosis does not require dense inflammation on the biopsy.

Simplified cross-sectional pattern

Pink fibers designate schematic injury

Schematic — not a clinical or histologic specimen

Slide 48 · Necrotizing myopathy: Clinical integration

Necrotizing pattern

Prominent myofiber injury

Relatively scant inflammation

Immune or toxic possibilities

Disease context

Anti-SRP / anti-HMGCR antibodies

Progressive weakness

Serum CK and drug history

Slide 49 · Rimmed vacuoles in inclusion body myositis

Rimmed vacuoles are characteristic abnormal cytoplasmic inclusions.

Established sporadic cases may also show endomysial T-cell inflammation.

Fibrosis and fatty replacement are frequent chronic features.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 50 · Inclusion body myositis spans two patterns

Inflammatory elements

Endomysial CD8-rich cells

Invasion of fibers

MHC class I upregulation

Degenerative elements

Rimmed vacuoles

Protein aggregates

Fibrosis / fatty replacement

Slide 51 · Direct toxic damage can cause myonecrosis

Drug / alcohol exposure

Direct myofiber injury

Necrosis with CK release

Severe: Possible rhabdomyolysis

Conceptual sequence — no numeric timing or quantitative scale

Slide 52 · Statin injury: Distinguish two processes

Direct toxicity

Acute necrotic injury

Exposure or dose context

May improve after withdrawal

Immune-mediated myopathy

Necrosis despite sparse inflammation

Anti-HMGCR can be present

Requires integrated assessment

Slide 53 · Lysosomal interference produces vacuolar change

Hydroxychloroquine and chloroquine can cause an insidious vacuolar myopathy.

Type I fibers may be predominantly affected.

Ultrastructural whorled lamellar membrane aggregates help characterize the lesion.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 54 · Mitochondrial injury is another route to myopathy

Zidovudine is cited as a drug capable of producing acquired mitochondrial myopathy.

Mitochondrial disturbance is mechanistically distinct from denervation.

Structural clues must be matched to exposure history.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 55 · Critical illness myopathy affects the sarcomere

Critical illness myopathy may feature selective loss of myosin thick filaments.

This is termed myosin-deficient myopathy in the source.

The resulting weakness can complicate recovery from mechanical ventilation.

Segment of a multinucleated myofiber

Disrupted thick-filament component

Schematic — not a clinical or histologic specimen

Slide 56 · Congenital core myopathy: Disrupted architecture

Central core disease features defined areas with disrupted sarcomeric arrangement.

These core regions contain fewer mitochondria.

The pattern contrasts with nonspecific segmental necrosis and regeneration.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 57 · Nemaline rods are structural inclusions

Nemaline myopathy produces spindle-shaped rods derived from Z-band material.

The source notes prominence in type I fibers.

Modified Gömöri trichrome or electron microscopy helps visualize the rods.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 58 · Central nuclei have different interpretations

Large nuclei with prominent nucleoli can indicate regeneration.

Centronuclear myopathies show nuclei persistently near the geometric center of fibers.

The nuclear finding must be interpreted with age, morphology, and context.

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 59 · A diagnostic pattern-first approach

Active damage: Necrosis / repair

Distribution: Scattered / grouped

Distinctive inclusions

Clinical + lab correlation

Conceptual sequence — no numeric timing or quantitative scale

Slide 60 · Biopsy patterns should be interpreted together

Morphologic finding

Interpretation

CK ↑

Damage signal; not subtype

Fiber distribution

Neurogenic vs myopathic clues

Necrosis + regeneration

Active injury–repair

Inclusions + remodeling

Subtyping and chronicity

Slide 61 · Teaching case: Elevated CK and necrotic fibers

Hypothetical patient with progressive weakness and increased CK.

Biopsy: Numerous necrotic and regenerating fibers but few inflammatory cells.

Question: Which source-described inflammatory-myopathy category warrants consideration?

Hypothetical teaching case

Simplified cross-sectional pattern

Pink fibers designate schematic injury

Schematic — not a clinical or histologic specimen

Slide 62 · Teaching case: Small fibers at fascicle edge

Hypothetical patient with proximal weakness and a cutaneous eruption.

Biopsy schematic: Peripheral fascicle fibers are selectively small.

Question: Which spatial atrophy pattern and disease association are illustrated?

Hypothetical teaching case

Arrangement within a muscle fascicle

Small fibers near fascicle edge

Schematic — not a clinical or histologic specimen

Slide 63 · Teaching case: Angulated fiber clusters

Hypothetical patient with progressive weakness and a peripheral neuropathic syndrome.

Biopsy schematic: Clusters of angulated atrophic myofibers.

Question: Does this favor primary myofiber degeneration or loss of innervation?

Hypothetical teaching case

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 64 · Teaching case: Vacuoles in a treated patient

Hypothetical patient receiving long-term hydroxychloroquine.

Muscle biopsy shows conspicuous vacuoles and unusual lysosomal structures.

Question: What exposure-related mechanism should be evaluated?

Hypothetical teaching case

Simplified cross-sectional pattern

Qualitative pattern only; Not a tissue section

Schematic — not a clinical or histologic specimen

Slide 65 · What the pathology report must communicate

Morphologic finding

Interpretation

Activity

Necrosis / myophagocytosis / regeneration

Chronicity

Dropout / fibrosis / adipose tissue

Topography

Grouped / perifascicular / selective

Specificity

Vacuoles, aggregates, clinical correlation

Slide 66 · Integrated summary

Direct myofiber injury causes segmental degeneration with CK release and macrophage clearance.

Satellite-cell fusion and sarcomere rebuilding drive regeneration; Chronic injury can end in fibrosis and fat.

Distribution and inclusion patterns discriminate among etiologies and neurogenic mimics.

Slide 67 · Primary reading

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026).

Chapter 27: Diseases of Skeletal Muscle; neurogenic and myopathic changes, with adjoining disease examples.

All diagnostic illustrations in this lecture are native editable schematics, not photographs of human biopsies.