Muscle Disease Pathology — Myopathies and Muscular Dystrophies

Molecular and Genetic Mechanisms

• Dystrophin deficiency and sarcolemmal instability: In DMD and Becker muscular dystrophy (BMD), mutations in the DMD gene (Xp21) lead to absent or abnormal dystrophin protein, a critical component of the dystrophin-associated protein complex (DAPC) that anchors the cytoskeleton to the sarcolemma. Loss of dystrophin results in mechanical destabilization during muscle contraction, leading to calcium influx through compromised sarcolemmal integrity, triggering proteolytic cascades and apoptosis.

• Calcium-mediated excitotoxicity and protein degradation: Uncontrolled intracellular calcium accumulation activates calcium-dependent proteases (calpains) and triggers mitochondrial dysfunction with reactive oxygen species (ROS) production. This calcium overload activates caspase-dependent and -independent apoptotic pathways, ultimately resulting in myofibril degeneration and fiber necrosis.

• Protein synthesis defects and quality control failure: In congenital myopathies (central core disease, nemaline myopathy), mutations in genes encoding sarcomeric proteins (RYR1, ACTA1, TPM3) or proteins involved in excitation-contraction coupling disrupt normal muscle physiology. Abnormal protein aggregation—including nemaline rod accumulation in nemaline myopathy and disorganized Z-disk material in myofibrillar myopathies—impairs contractile function and proteasomal degradation capacity.

• Mitochondrial dysfunction and energy failure: In mitochondrial myopathies (e.g., MELAS, Leigh syndrome), mutations in mitochondrial DNA or nuclear genes encoding respiratory chain components impair ATP production, leading to ragged-red fiber formation due to accumulation of abnormal mitochondria. Defective oxidative metabolism results in energy depletion particularly affecting high-energy-demand muscle tissue.

• Immune-mediated myocyte destruction: In inflammatory myopathies (polymyositis, dermatomyositis, inclusion body myositis), CD8+ T-cell infiltrates targeting sarcolemmal antigens and MHC class I upregulation on muscle fibers drive autoimmune-mediated myonecrosis. Polymyositis is characterized by endomysial inflammatory infiltrates surrounding and invading non-necrotic fibers; dermatomyositis involves perifascicular atrophy due to microvascular disease and perimysial inflammation.

Cellular and Morphological Consequences

• Myofibril disorganization: Loss of proper Z-disk alignment and sarcomeric architecture results in loss of contractile force and mechanical efficiency.

• Fiber necrosis and regeneration cycling: Repeated cycles of fiber necrosis with phagocytic infiltration and abortive fiber regeneration (evidenced by centrally located nuclei in regenerating fibers) lead to progressive muscle fiber loss.

• Fibrosis and fatty infiltration: Degenerated muscle is replaced by endomysial fibrosis and adipose tissue, creating a "moth-eaten" appearance on light microscopy and characteristic T2 hyperintensity with fat infiltration on MRI.

Genetic/Inherited Myopathies

• Muscular dystrophies
• X-linked: DMD (dystrophin gene, most common, severe form), BMD (same gene, milder form), Emery-Dreifuss muscular dystrophy (EMD gene, lamin A/C)
• Autosomal dominant: Myotonic dystrophy (DMPK repeat expansion), facioscapulohumeral dystrophy (FSHD, D4Z4 repeats), oculopharyngeal myopathy
• Autosomal recessive: Limb-girdle muscular dystrophy (LGMD, ~20 subtypes, including sarcoglycan, calpain-3, dysferlin mutations)

• Congenital myopathies (usually autosomal dominant or recessive)
• Central core disease (RYR1, SEPN1 mutations)
• Nemaline myopathy (NEB, ACTA1, TPM3 mutations)
• Centronuclear/myotubular myopathy (MTM1 in X-linked form)
• Congenital fiber type disproportion

• Metabolic myopathies
• Glycogen storage diseases (GSD): McArdle disease (myophosphorylase deficiency, GSD V), Pompe disease (acid alpha-glucosidase deficiency, GSD II), Cori disease (GSD III)
• Lipid storage myopathies: Carnitine deficiency, CPT II deficiency
• Mitochondrial myopathies: Point mutations or deletions in mtDNA (MELAS, MERRF), or nuclear gene mutations affecting respiratory chain (Leigh syndrome)

Acquired Myopathies

• Inflammatory myopathies (idiopathic)
• Polymyositis (PM)
• Dermatomyositis (DM), including cancer-associated myositis
• Inclusion body myositis (IBM), most common acquired myopathy in elderly
• Immune-mediated necrotizing myopathy (anti-HMGCR, anti-SRP)

• Drug and toxin-induced
• Statins (HMG-CoA reductase inhibitors)
• Corticosteroids (critical illness myopathy, vacuolar myopathy with prolonged use)
• Alcohol (acute and chronic toxic myopathy)
• Zidovudine (antiretroviral myopathy)

• Endocrine/metabolic
• Thyroid disease (hypothyroid myopathy, thyroid storm myopathy)
• Cushing syndrome and corticosteroid-induced myopathy
• Diabetes mellitus

• Associated with systemic disease
• Sarcoidosis, systemic lupus erythematosus, mixed connective tissue disease
• Amyloidosis, light chain deposits

Risk Factors

• Genetic inheritance pattern (autosomal dominant, recessive, X-linked, mitochondrial)
• Family history of neuromuscular disease
• Environmental exposures: Alcohol, statin use, statins in combination with other medications
• Age of onset: Congenital myopathies present in infancy; DMD presents in early childhood; adult-onset myositis typically after age 30 (IBM >50 years)
• Female carrier status in X-linked disorders (variable manifestations due to X-inactivation)

Cardinal Symptoms and Signs

• Progressive proximal muscle weakness
• Difficulty with climbing stairs, rising from chair (gluteal/quadriceps weakness)
• Difficulty with overhead activities, hair combing (shoulder/deltoid weakness)
• Weakness typically symmetric and progressive in dystrophies; may be asymmetric or multifocal in myositis
• In DMD: onset by age 3-5 years with difficulty running, frequent falls, difficulty climbing stairs; by early teens, wheelchair-dependent

• Myalgia and muscle tenderness
• Prominent in inflammatory myopathies (polymyositis, dermatomyositis) and acute toxic myopathies
• May be absent or mild in genetic dystrophies
• Pain with muscle stretch in some metabolic myopathies (exercise-induced)

• Muscle atrophy and wasting
• Selective involvement in dystrophies: quadriceps atrophy in LGMD; pectoralis atrophy in FSHD; facial muscles in myotonic dystrophy
• Pseudohypertrophy: particularly in DMD, where degenerating muscle is replaced by fat and connective tissue, paradoxically enlarging calf muscles while decreasing strength
• Generalized atrophy in inflammatory myositis and advanced dystrophies

• Skin manifestations (particularly dermatomyositis)
• Heliotrope rash: violaceous periorbital edema
• Gottron papules: symmetric erythematous papules over dorsal interphalangeal and metacarpophalangeal joints
• Shawl sign: erythema over shoulders and upper chest
• Mechanics hands: hyperkeratosis and fissuring of lateral fingers

• Systemic features (myositis and some dystrophies)
• Constitutional symptoms (fever, malaise, weight loss) in active myositis
• Dysphagia and dysphonia (esophageal/pharyngeal involvement in polymyositis, inclusion body myositis, myotonic dystrophy)
• Respiratory muscle weakness: leads to hypoventilation, obstructive sleep apnea, orthopnea; life-threatening in advanced DMD and severe myositis

• Cardiac involvement
• Dilated cardiomyopathy in DMD (progressive), dystrophin-related cardiomyopathy in BMD, and myotonic dystrophy
• Conduction abnormalities, arrhythmias
• Heart failure a leading cause of death in DMD

• Contractures and skeletal deformities (dystrophies)
• Equinovarus deformities from Achilles tendon contracture (DMD)
• Hip, knee flexion contractures limiting ambulation
• Scoliosis (develops in >80% of DMD patients; accelerates after loss of ambulation)

Physical Examination Findings

• Gower sign: characteristic finding in DMD where patient uses upper extremity muscles to "climb up" their legs to rise from sitting (demonstrates severe hip/thigh weakness)
• Winged scapula: prominence of medial scapular border due to serratus anterior weakness (seen in LGMD, myotonic dystrophy, IBM)
• Trendelenburg gait: pelvic dropping during gait due to hip abductor weakness
• Waddle gait: broad-based gait compensating for hip weakness
• Calf pseudohypertrophy: firm, enlarged muscle due to fat infiltration (DMD, LGMD)
• Myotonia: prolonged muscle contraction after voluntary effort (myotonic dystrophy, myotonia congenita); demonstrates delayed relaxation on percussion
• Facial weakness: ptosis, decreased facial expressivity (myasthenia gravis must be ruled out), temporalis atrophy
• Ocular involvement: external ophthalmoplegia (oculopharyngeal myopathy, mitochondrial myopathy); ptosis
• Hyporeflexia or areflexia: reduced or absent deep tendon reflexes despite preserved strength (sometimes seen in IBM)

Laboratory Findings

• Markedly elevated creatine kinase (CK)
• DMD: CK >5,000-20,000 IU/L (up to 100-fold normal)
• Polymyositis/dermatomyositis: CK 1,000-10,000 IU/L
• Inclusion body myositis: often normal or mildly elevated despite significant weakness
• Metabolic myopathies: variable elevation, may be normal at rest

• Myoglobinuria: indicates severe muscle damage; dark-colored ("tea-colored") urine; indicates risk of acute kidney injury from pigment precipitation in renal tubules
• Elevated transaminases (AST, ALT): from muscle damage; creatinine typically normal (kidney function preserved)
• Autoantibodies in myositis
• Anti-Jo1 (histidyl-tRNA synthetase): associated with anti-synthetase syndrome; polymyositis, interstitial lung disease, arthritis
• Anti-Mi-2: strongly associated with dermatomyositis
• Anti-SRP (signal recognition particle): immune-mediated necrotizing myopathy
• Anti-HMGCR (HMG-CoA reductase): statin-associated immune myopathy
• Anti-TIF1γ, anti-NXP2: dermatomyositis, often cancer-associated

• Muscle-specific antibodies: in mitochondrial myopathy (anti-mitochondrial antibodies), in metabolic myopathy screening

Histopathology and Microscopy

Muscular Dystrophies (General Features)

• Light microscopy findings
• Fiber size variation (marked): combination of atrophic fibers (small, dark-staining) and hypertrophic fibers
• Myofibrillar disorganization: loss of normal Z-disk alignment, moth-eaten appearance
• Central nucleation: nuclei move to center of fiber, indicating regenerating fibers (normal nuclei are peripheral)
• Connective tissue proliferation: endomysial fibrosis with collagen deposition (demonstrated with trichrome stain); perimysial fibrosis
• Fatty infiltration: replacement of muscle by adipose tissue
• Necrotic and regenerating fibers: scattered throughout
• Inflammatory infiltrate: variable, may be present but not prominent (unlike myositis)

Duchenne/Becker Muscular Dystrophy (DMD/BMD)

• Dystrophin immunostaining (immunofluorescence or immunohistochemistry): absent in DMD (gold standard finding); reduced or patchy in BMD or female carriers
• Structural abnormalities: Subsarcolemmal membrane disruption on electron microscopy
• Fiber necrosis predominates, particularly in DMD; regeneration ongoing but overwhelmed

Congenital Myopathies

• Central core disease
• Core lesions: central regions of muscle fibers lacking oxidative enzyme staining (appear dark/empty on NADH stain)
• Cores typically don't contain Z-disk material
• Muscle architecture otherwise relatively preserved compared to dystrophies

• Nemaline myopathy
• Nemaline rods (also called rod bodies): eosinophilic, rod-shaped inclusions in sarcoplasm, visible on H&E and enhanced on trichrome stain
• Rods are composed of α-actinin and other Z-disk material
• Type 1 fiber predominance (slow fibers preferentially affected)
• Generally less fibrosis and fatty infiltration than dystrophies

• Centronuclear myopathy
• Central nucleation: prominent feature; nuclei arranged in rows through fiber centers
• Radial splay pattern: myofibrils radiating outward from central nucleus (distinctive on transverse section)
• Minimal fibrosis; fibers often of normal size

Inflammatory Myopathies

• Polymyositis
• Endomysial inflammation: lymphocytic infiltrate composed primarily of CD8+ T cells surrounding and invading non-necrotic muscle fibers (diagnostic hallmark; distinguishes from dermatomyositis)
• Fiber necrosis and regeneration
• Variable fiber size; no perifascicular atrophy
• Nuclear and cytoplasmic inclusions may be present (inclusion body myositis variant)

• Dermatomyositis
• Perifascicular atrophy: atrophy of muscle fibers at periphery of fascicles (pathognomonic finding)
• **Pe

Immediate stabilisation

• Malignant hyperthermia crisis (*RYR1*-related core myopathy, exposure to volatile anaesthetic or succinylcholine): stop the trigger, give 100% oxygen, and administer the ryanodine-receptor antagonist dantrolene immediately with active cooling — the Malignant Hyperthermia Association of the United States (MHAUS) protocol. Treat hyperkalaemia and acidosis concurrently.
• Rhabdomyolysis with myoglobinuria: aggressive isotonic IV crystalloid to maintain urine output and prevent pigment cast nephropathy; monitor potassium and ECG for peaked T waves.

Duchenne/Becker muscular dystrophy

• Glucocorticoids (prednisone or deflazacort) remain the mainstay of disease-modifying therapy and are the best-established agents for prolonging ambulation and delaying scoliosis; the AAN practice guideline on corticosteroid treatment in DMD and the CDC-sponsored DMD Care Considerations endorse initiation once motor gains plateau. Newer FDA-approved adjuncts — the dissociative steroid vamorolone and the histone deacetylase inhibitor givinostat — have shown slowing of functional decline.
• Mutation-specific therapy: antisense oligonucleotide exon-skipping agents (e.g., eteplirsen for exon 51–amenable deletions) and FDA-approved adeno-associated viral micro-dystrophin gene transfer (approval pathway and age eligibility have evolved — check current labeling); eligibility is determined by genotype, not biopsy.
• Cardiac surveillance and therapy: ACE inhibitor or ARB started before overt dysfunction, with beta blocker and mineralocorticoid receptor antagonist added as EF falls, per ACC/AHA heart failure guidance; SGLT2 inhibitors complete guideline-directed therapy once HFrEF is established.
• Respiratory support: nocturnal noninvasive positive-pressure ventilation guided by FVC and hypercapnia, plus cough-assist, per the DMD Care Considerations respiratory recommendations.

Inflammatory myopathies

• Systemic corticosteroids are first-line for dermatomyositis, polymyositis, and immune-mediated necrotizing myopathy.
• Steroid-sparing escalation: methotrexate or azathioprine early; IVIG (FDA-approved for dermatomyositis) or rituximab for refractory disease; mycophenolate or calcineurin inhibitors when interstitial lung disease dominates. For the cutaneous disease of dermatomyositis, strict photoprotection plus hydroxychloroquine is standard practice.
• Statin-associated myopathy: stop the statin; anti-HMGCR necrotizing myopathy does not remit with withdrawal alone and requires immunosuppression.

Contraindicated / avoid

• Succinylcholine and volatile anaesthetics in dystrophinopathy and core myopathy — risk of hyperkalaemic cardiac arrest and MH.
• Immunosuppression in inclusion body myositis — ineffective and exposes the patient to steroid myopathy.
• Enzyme replacement (alglucosidase alfa) is disease-specific to Pompe disease and has no role in other myopathies.

Disease-related — emergencies flagged

• Respiratory failure (emergency): diaphragm and intercostal weakness cause hypoventilation; signals are falling FVC, morning headache, orthopnoea, and rising PaCO₂. Leading cause of death in advanced DMD and severe myositis.
• Dilated cardiomyopathy and arrhythmia (emergency when decompensated): dystrophin loss in cardiomyocytes produces the same sarcolemmal fragility as in skeletal muscle; falling ejection fraction on surveillance echocardiography or cardiac MRI late gadolinium enhancement is the signal.
• Conduction block in myotonic dystrophy (emergency): fibrosis of the His–Purkinje system causes progressive PR and QRS prolongation and sudden cardiac death; a widening QRS or new AV block prompts pacemaker consideration.
• Rhabdomyolysis with acute kidney injury (emergency): pigment cast nephropathy after exertion in metabolic myopathy or acute necrotizing myopathy; tea-coloured urine with dipstick blood but no red cells on microscopy.
• Aspiration pneumonia: pharyngeal and oesophageal striated muscle weakness in IBM, polymyositis, and myotonic dystrophy; recurrent lower-lobe infiltrates.
• Interstitial lung disease: strongly linked to anti-Jo1 and other antisynthetase antibodies; dyspnoea with restrictive spirometry and reduced DLCO. Rapidly progressive ILD is an emergency.
• Occult malignancy in dermatomyositis: paraneoplastic mechanism, highest with anti-TIF1γ; unexplained weight loss or refractory disease should trigger age- and sex-appropriate cancer screening.
• Scoliosis and contractures: unopposed pull across joints after ambulation is lost; restrictive lung disease follows.
• Calcinosis cutis: dystrophic calcification, characteristic of juvenile dermatomyositis.

Treatment-related

• Glucocorticoids: osteoporosis with vertebral compression fracture, cataracts, growth suppression, weight gain, hyperglycaemia, and adrenal suppression. Steroid myopathy is the key trap — worsening proximal weakness with a normal or falling CK signals drug effect, not disease flare.
• IVIG: thrombosis, aseptic meningitis, and osmotic renal injury.
• Rituximab: hypogammaglobulinaemia, hepatitis B reactivation, and rarely PML — screen serology before dosing.
• Methotrexate: hepatotoxicity and pneumonitis, which can mimic myositis-associated ILD.

• **Boy age 3–5 with Gower sign, calf pseudohypertrophy, and CK in the thousands: the single best next step is genetic testing** (deletion/duplication analysis, then sequencing), not muscle biopsy. Biopsy with dystrophin immunostaining is reserved for genetically negative cases — a common distractor is to jump to biopsy.
• **Perifascicular atrophy = dermatomyositis; CD8+ endomysial invasion of non-necrotic fibers = polymyositis.** The mechanism differs: DM is complement-mediated capillary injury causing watershed ischaemia at the fascicle edge; PM is direct cytotoxic T-cell killing.
• New dermatomyositis in an adult demands age- and sex-appropriate malignancy screening — this is the association examiners test most, especially with anti-TIF1γ.
• Inclusion body myositis is the trap in an elderly patient: asymmetric finger-flexor and quadriceps weakness, only mildly elevated CK, rimmed vacuoles on biopsy, and no response to steroids. Choosing prednisone is the wrong answer.
• Ragged red fibers on Gómöri trichrome with maternal inheritance and variable severity between siblings (heteroplasmy) points to a mitochondrial myopathy — MELAS, MERRF (myoclonic epilepsy).
• McArdle disease (GSD V): exercise intolerance with a second-wind phenomenon; ischaemic forearm exercise shows no rise in lactate but a normal ammonia rise. If ammonia also fails to rise, the test was not performed adequately.
• Myotonic dystrophy type 1: CTG expansion in DMPK, anticipation, grip myotonia with delayed relaxation, frontal balding, posterior subcapsular cataracts, testicular atrophy, insulin resistance — and cardiac conduction disease that kills.
• Never give succinylcholine to a boy with undiagnosed weakness and high CK — hyperkalaemic cardiac arrest under anaesthesia is a classic DMD presentation. Volatile anaesthetics plus RYR1 mutation trigger malignant hyperthermia, treated with dantrolene.