Physiology of Muscles
Physiology of Muscles
What Do You Need to Know?
- Sarcomere anatomy — A-band (dark, myosin), I-band (light, actin only), H-zone (myosin only), Z-line (sarcomere boundary), M-line (center)
- Excitation-contraction coupling — AP → T-tubule → DHP receptor → RyR → Ca²⁺ release → troponin C binding → cross-bridge cycling
- Fiber types — Type I (slow, oxidative, red, fatigue-resistant) vs Type II (fast, glycolytic, white, fatigable)
- Motor unit — Henneman size principle: small motor neurons recruited first
- Metabolic myopathies — McArdle (myophosphorylase, second wind), Pompe (acid maltase, respiratory failure), CPT II (recurrent rhabdomyolysis)
- Myopathic vs neuropathic patterns — proximal vs distal weakness, EMG and biopsy distinctions
- Key dystrophies — DMD/BMD (dystrophin), DM1 vs DM2, FSHD, LGMD
- Biopsy patterns — ragged red fibers (mito), rimmed vacuoles (IBM), perifascicular atrophy (DM), fiber type grouping (reinnervation)
🚩 Don’t Miss — Test-Day Priorities
- A-band stays constant: During contraction the I-band & H-zone shorten as Z-lines approach — the A-band length is unchanged. Single most-tested sarcomere fact.
- DHPR ↔ RYR1 mechanical coupling: Skeletal EC coupling does NOT require extracellular Ca²⁺ influx — T-tubule DHPR (voltage sensor) directly opens RYR1 on SR. Cardiac (RYR2) uses Ca-induced Ca release.
- Rigor mortis = no ATP: Myosin needs ATP to DETACH from actin (not to bind). Loss of ATP after death locks cross-bridges.
- Henneman size principle: Smallest (Type I, low-threshold) motor units recruited first; largest (Type IIx/b) last as force demand ↑.
- Malignant hyperthermia: RYR1 (or CACNA1S) gain-of-function + volatile anesthetic / succinylcholine → masseter spasm, hyperthermia, rhabdo, hyperkalemia. Treat with dantrolene + cooling.
- Type II atrophy = disuse / steroid / endocrine: Steroid myopathy, Cushing, hyperthyroid, paraneoplastic & disuse selectively atrophy Type II fibers (proximal, painless, normal CK).
- Fiber type grouping = reinnervation: Loss of normal mosaic checkerboard on ATPase stain = chronic neurogenic process (axonal sprouting from surviving motor neurons).
- Metabolic myopathy red flags: Exercise-induced cramps + myoglobinuria → think McArdle (PYGM, “second wind”), CPT-II (long exercise/fasting, adult rhabdo), or MH-spectrum (RYR1).
- Neonatal AChR γ → ε switch: Fetal γ-subunit replaced by adult ε-subunit perinatally — relevant to slow-channel/fast-channel congenital myasthenic syndromes.
- Dystroglycan complex links cytoskeleton to ECM: Dystrophin → β-dystroglycan → α-dystroglycan → laminin. Disruption → DMD/BMD, LGMD, dystroglycanopathies (Walker-Warburg, MEB, FCMD).
🔍 Buzzwords & Pathognomonic FindingsStructure / EC coupling · Fiber types / metabolism · Disease / drug
Structure / EC coupling
- Z-line α-actinin → anchors thin (actin) filaments — sarcomere boundary
- M-line myomesin → anchors thick (myosin) filaments at sarcomere center
- A-band unchanged, I/H shrink → sliding filament theory (contraction)
- Troponin C binds Ca²⁺ → tropomyosin shift → exposes actin myosin-binding sites
- DHPR (CACNA1S, L-type) → T-tubule voltage sensor mechanically gates RYR1
- RYR1 on SR → Ca²⁺ release channel for skeletal EC coupling (RYR2 = cardiac)
- SERCA + phospholamban → pumps Ca²⁺ back into SR (relaxation)
- Myosin ATPase → powers cross-bridge cycle; ATP needed to DETACH (rigor if absent)
Fiber types / metabolism
- Type I — slow oxidative, red → high myoglobin/mitochondria, fatigue-resistant, postural, MyHC-I
- Type IIa — fast oxidative-glycolytic, pink → moderate fatigue, MyHC-IIa
- Type IIx/IIb — fast glycolytic, white → anaerobic, high force, rapid fatigue, sprinting
- ATPase pH 9.4 dark → Type II (reversed at pH 4.3 → Type I dark)
- SDH / NADH-TR dark → Type I (mitochondria-rich) on oxidative stains
- Henneman size principle → small motor units recruited first; rate coding modulates force
- Creatine phosphate & creatine kinase → immediate ATP buffer (first ~10 sec)
- Carnitine palmitoyl shuttle → imports long-chain fatty acyl-CoA into mitochondria for β-oxidation
- Satellite cells (Pax7+) → quiescent muscle stem cells under basal lamina; MyoD activation → regeneration
Disease / drug association
- Malignant hyperthermia → RYR1 / CACNA1S + volatiles / succinylcholine → dantrolene
- Central core disease → RYR1 congenital myopathy + MH susceptibility
- Caffeine-halothane contracture test → gold-standard MH susceptibility screen
- McArdle disease → PYGM (myophosphorylase) deficiency, “second wind” phenomenon, flat lactate on ischemic forearm test
- CPT-II deficiency (adult) → exercise/fasting-induced rhabdomyolysis & myoglobinuria
- Rhabdomyolysis labs → CK ≥ 5× ULN, myoglobinuria, hyperK, hyperphos, HYPOcalcemia, AKI, ↑ uric acid
- Ragged-red & COX-negative fibers → mitochondrial myopathy (oxidative phosphorylation failure)
- Fiber type grouping + angulated fibers → chronic neurogenic reinnervation
- Selective Type II atrophy → steroid / disuse / thyrotoxic / Cushing / paraneoplastic myopathy
- Dystrophin / dystroglycan / sarcoglycan loss → DMD & BMD / dystroglycanopathy / LGMD
- Neonatal γ → ε AChR subunit switch → relevant to congenital myasthenic syndromes (slow/fast channel)
Muscle Fiber Structure
Sarcomere Anatomy
The sarcomere is the basic contractile unit, bounded by two Z-lines.
| Structure | Location | Composition | Board-Relevant Detail |
|---|---|---|---|
| A-band | Center of sarcomere | Thick (myosin) +/- overlapping thin filaments | Does NOT change length during contraction (Anisotropic, dArk). Memory aid: A-band = Always the same length — the single most tested sarcomere fact. |
| I-band | Between A-bands of adjacent sarcomeres | Thin filaments only (actin) | Shortens during contraction (Isotropic, lIght) |
| H-zone | Center of A-band | Myosin only (no actin overlap) | Shortens during contraction; disappears at full contraction |
| Z-line (Z-disc) | Sarcomere boundary | Alpha-actinin anchors actin | Defines sarcomere; Z-to-Z = one sarcomere |
| M-line | Center of H-zone | Myomesin; anchors myosin | Middle of sarcomere |
Board Pearl
During contraction, the A-band stays the same length. The I-band and H-zone shorten as actin slides over myosin (sliding filament theory). This is the most commonly tested sarcomere fact.
Thick vs Thin Filaments
| Filament | Main Protein | Associated Proteins | Function |
|---|---|---|---|
| Thick | Myosin (heavy chains) | Myosin light chains; titin spans Z-line to M-line (third filament system); provides passive elasticity, anchors thick filament, mechanosensing. (Largest known protein.) | Cross-bridge formation; ATPase activity in myosin head |
| Thin | Actin (F-actin polymer) | Tropomyosin, Troponin complex (T, C, I) | Troponin C binds Ca²⁺ → tropomyosin shifts → exposes myosin-binding site |
Troponin Subunits
- Troponin C — binds Calcium (the Ca²⁺ sensor)
- Troponin T — binds Tropomyosin (attaches complex to thin filament)
- Troponin I — Inhibits actin-myosin interaction (holds tropomyosin in blocking position)
T-Tubules and Sarcoplasmic Reticulum
- T-tubules (transverse tubules) — invaginations of the sarcolemma that carry the action potential deep into the muscle fiber
- Sarcoplasmic reticulum (SR) — intracellular Ca²⁺ store; terminal cisternae flank T-tubules forming the triad
- Triad = 1 T-tubule + 2 terminal cisternae (located at the A-I band junction in skeletal muscle)
- DHP receptor (dihydropyridine receptor) — voltage sensor on T-tubule membrane
- RyR1 (ryanodine receptor) — Ca²⁺ release channel on SR; mechanically coupled to DHP receptor in skeletal muscle
Board Pearl
Malignant hyperthermia results from a mutation in the RyR1 gene (less commonly CACNA1S, DHPR α1 subunit) → uncontrolled Ca²⁺ release from SR → sustained contraction, hyperthermia, rhabdomyolysis. Triggered by volatile anesthetics and succinylcholine. Treat with dantrolene (blocks RyR1).
Excitation-Contraction Coupling
Steps from AP to Contraction
- Action potential propagates along sarcolemma and into T-tubules
- DHP receptor (voltage-gated L-type Ca²⁺ channel) senses depolarization
- DHP receptor mechanically activates RyR1 on the SR (skeletal muscle = mechanical coupling; cardiac muscle = Ca²⁺-induced Ca²⁺ release)
- Ca²⁺ floods the sarcoplasm from SR terminal cisternae
- Ca²⁺ binds troponin C → conformational change in troponin complex
- Tropomyosin shifts away from myosin-binding sites on actin
- Cross-bridge cycling begins (myosin head binds actin, power stroke, release)
Cross-Bridge Cycle
- Attachment — myosin head (with ADP + Pi bound) binds actin
- Power stroke — Pi released → myosin head pivots → actin pulled toward M-line; ADP released
- Rigor state — myosin tightly bound to actin (no nucleotide); this is the basis of rigor mortis
- Detachment — new ATP binds myosin → myosin detaches from actin
- Re-cocking — ATP hydrolyzed to ADP + Pi → myosin head returns to high-energy position
Board Pearl
ATP is needed for both contraction AND relaxation. Without ATP, myosin cannot detach from actin → rigor mortis. This is why muscle stiffness occurs after death (ATP depletion).
Relaxation
- SERCA pump (SR Ca²⁺-ATPase) actively pumps Ca²⁺ back into the SR
- Ca²⁺ dissociates from troponin C → tropomyosin re-covers myosin-binding sites
- Cross-bridge cycling stops → muscle relaxes
- Phospholamban — inhibits SERCA in cardiac muscle; phosphorylation by PKA (beta-adrenergic stimulation) removes inhibition → faster relaxation (lusitropy)
Clinical Pearl
Brody disease (rare) results from SERCA1 deficiency → impaired muscle relaxation → exercise-induced muscle stiffness without electrical myotonia on EMG. Distinguished from true myotonia by electrically silent stiffness.
Muscle Fiber Types
Type I vs Type II Comparison
💎 Fiber Type Memory Aid
| Type | Think |
|---|---|
| Type I (slow oxidative) | Marathon runner — red, fatigue-resistant, high mitochondria/myoglobin |
| Type IIa (fast oxidative-glycolytic) | Middle-distance athlete — intermediate properties; some endurance with speed |
| Type IIb/IIx (fast glycolytic) | Sprinter — white, fatigable, low mitochondria, anaerobic burst power |
| Feature | Type I (Slow Oxidative) | Type IIa (Fast Oxidative-Glycolytic) | Type IIb/IIx (Fast Glycolytic) |
|---|---|---|---|
| Color | Red (high myoglobin) | Intermediate | White (low myoglobin) |
| Mitochondria | Abundant | Many | Few |
| Metabolism | Oxidative (aerobic) | Mixed | Glycolytic (anaerobic) |
| Fatigue resistance | High (endurance) | Moderate | Low (quick fatigue) |
| Motor unit size | Small | Medium | Large |
| Contraction speed | Slow | Fast | Fast |
| ATPase staining (pH 9.4) | Light | Intermediate | Dark |
| Function | Posture, sustained activity | Walking, moderate activities | Sprinting, jumping, powerful bursts |
| Example muscle | Soleus, paraspinals | — | Gastrocnemius (lateral head), biceps brachii (fast-glycolytic muscles) |
Clinical Relevance of Fiber Type
| Pattern | Associated Conditions |
|---|---|
| Type I fiber atrophy | Myotonic dystrophy type 1, congenital myopathies (nemaline, central core) |
| Type II fiber atrophy | Steroid myopathy, disuse, cachexia, aging (sarcopenia), upper motor neuron lesions |
| Fiber type grouping | Chronic reinnervation (neuropathic process) |
| Type I predominance | Endurance athletes, central core disease |
Board Pearl
Type II fiber atrophy = steroid myopathy, disuse, cachexia. Type II fibers are the "expendable" fibers lost first in catabolic states. CK is typically normal in steroid myopathy — this helps distinguish it from inflammatory myopathy flares.
Motor Unit
Definition and Components
- Motor unit = one alpha motor neuron + all the muscle fibers it innervates
- The innervation ratio = number of muscle fibers per motor neuron
- Small ratio (e.g., extraocular muscles ~3:1) → fine control
- Large ratio (e.g., quadriceps ~2000:1) → gross power
Henneman Size Principle
- Small motor neurons (low threshold) are recruited first → Type I (slow) fibers
- Large motor neurons (high threshold) are recruited later → Type II (fast) fibers
- Orderly recruitment: low force → high force demands
- This ensures smooth, graded muscle contraction
Force Modulation
- Recruitment — activating more motor units (primary method at low forces)
- Rate coding — increasing firing rate of active motor units (primary method at high forces)
- Tetanus — sustained contraction when stimulation frequency exceeds ability to relax between stimuli
Clinical Pearl
After denervation, surviving motor neurons sprout collateral branches to reinnervate orphaned muscle fibers → larger motor units → large, polyphasic MUPs on EMG and fiber type grouping on biopsy. These are hallmarks of chronic neuropathic processes.
Energy Metabolism
ATP Sources in Muscle
| Energy Source | Duration | Speed | When Used |
|---|---|---|---|
| Creatine phosphate (phosphocreatine) | ~10 seconds | Immediate | First seconds of intense activity; creatine kinase transfers phosphate to ADP |
| Anaerobic glycolysis | ~1–2 minutes | Fast | Short bursts; glucose → lactate; produces 2 ATP/glucose |
| Oxidative phosphorylation | Hours | Slow onset | Sustained activity; uses fatty acids, glucose, amino acids; produces ~36 ATP/glucose |
Metabolic Myopathies
| Disease | Enzyme Defect | Key Features | Board Hallmark |
|---|---|---|---|
| McArdle disease (GSD V) | Myophosphorylase | Exercise intolerance, cramps, myoglobinuria | "Second wind" phenomenon; no lactate rise on forearm exercise test |
| Pompe disease (GSD II) | Acid maltase (α-glucosidase) | Infantile: cardiomyopathy, hypotonia, death by 2 yrs; Late-onset: proximal weakness, respiratory failure | Diaphragm weakness out of proportion to limb weakness; ERT (alglucosidase alfa) available |
| Tarui disease (GSD VII) | Phosphofructokinase | Similar to McArdle but with hemolytic anemia | "Out of wind" phenomenon (glucose worsens symptoms); hemolysis |
| CPT II deficiency | Carnitine palmitoyltransferase II | Recurrent myoglobinuria with prolonged exercise, fasting, cold, illness | Most common cause of recurrent rhabdomyolysis in adults; normal strength between attacks |
| Primary carnitine deficiency | Carnitine transporter (OCTN2) | Cardiomyopathy, weakness, hypoglycemia | Low serum carnitine; responds to carnitine supplementation |
Board Pearl
McArdle = second wind (feels better after 10–15 min as blood-borne glucose AND free fatty acid delivery increases, not fatty acid alone). Tarui = out of wind (glucose worsens symptoms by blocking fatty acid utilization). Both show no lactate rise on forearm exercise test. CPT II deficiency triggers: prolonged exercise, fasting, cold, infection.
Forearm Exercise Test
- Normal: lactate rises with exercise; ammonia rises
- Glycolytic defects (McArdle, Tarui): no lactate rise, ammonia rises normally
- Myoadenylate deaminase deficiency: lactate rises normally, no ammonia rise
Muscle Pathology Patterns
Myopathic vs Neuropathic
| Feature | Myopathic | Neuropathic |
|---|---|---|
| Weakness distribution | Proximal > distal (hip/shoulder girdle) | Distal > proximal (feet/hands first) |
| Reflexes | Preserved until late (proportional to weakness) | Decreased early (LMN) or increased (UMN) |
| Atrophy | Mild, late; may have pseudohypertrophy | Prominent, early |
| Fasciculations | Absent | Present (LMN) |
| Sensory loss | Absent | May be present (peripheral neuropathy) |
| CK | Elevated (often markedly) | Normal or mildly elevated |
| EMG — MUPs | Small amplitude, short duration, polyphasic | Large amplitude, long duration, polyphasic |
| EMG — Recruitment | Early (full) recruitment | Reduced recruitment (fast-firing units) |
| EMG — Fibrillations | Present in inflammatory/necrotic myopathies | Present (active denervation) |
| Biopsy | Fiber size variation, central nuclei, necrosis/regeneration, +/- inflammation | Grouped atrophy, fiber type grouping, target fibers, angular atrophic fibers |
Board Pearl
Myopathic EMG = small, short, polyphasic MUPs with early (full) recruitment. Neuropathic EMG = large, long, polyphasic MUPs with reduced recruitment. The key exception is IBM, which shows a mixed pattern (both myopathic and neuropathic features).
Dystrophic Features on Biopsy
- Marked fiber size variation (hypertrophic and atrophic fibers)
- Increased internal (central) nuclei
- Fiber splitting
- Necrosis and regeneration (basophilic regenerating fibers)
- Fibrosis and fatty replacement (endomysial connective tissue proliferation)
- Absent or reduced immunostaining for specific proteins (e.g., dystrophin in DMD)
Key Dystrophies
Comparison Table
| Dystrophy | Gene / Protein | Inheritance | Key Features | Board Hallmark |
|---|---|---|---|---|
| Duchenne (DMD) | DMD gene / dystrophin absent | X-linked | Onset 2–5 yrs; calf pseudohypertrophy; Gowers sign; wheelchair by 12; cardiomyopathy; CK >10,000 | Frameshift/nonsense mutation → no dystrophin |
| Becker (BMD) | DMD gene / dystrophin reduced/abnormal | X-linked | Later onset; milder; ambulation into adulthood; cardiomyopathy can be severe and out of proportion to skeletal weakness | In-frame deletion → partially functional dystrophin |
| Myotonic dystrophy type 1 (DM1) | DMPK / CTG trinucleotide repeat | AD | Distal weakness; grip myotonia; cataracts; cardiac conduction defects; frontal balding; testicular atrophy; insulin resistance | "Hatchet face"; anticipation (congenital form = severe) |
| Myotonic dystrophy type 2 (DM2) | CNBP / CCTG tetranucleotide repeat | AD | Proximal weakness; milder myotonia; muscle pain prominent; no congenital form | Proximal > distal (opposite of DM1); pain is prominent |
| FSHD | D4Z4 contraction (chr 4q35) / DUX4; FSHD2 mediated by SMCHD1 (or DNMT3B/LRIF1) hypomethylation without D4Z4 contraction; both subtypes converge on DUX4 expression | AD | Face → scapula → humerus; scapular winging; asymmetric; can’t whistle or close eyes tightly | Facial + scapular weakness; highly asymmetric |
| LGMD | Multiple genes (>30 subtypes); examples: LGMD-R1 calpainopathy, LGMD-R2 dysferlinopathy, LGMD-R3-R6 sarcoglycanopathies, LGMD-D1 DNAJB6 | AD or AR | Proximal limb-girdle weakness; variable onset; heterogeneous | Genetically heterogeneous; requires genetic testing for subtype |
| Emery-Dreifuss | Emerin or Lamin A/C | X-linked or AD | Humeroperoneal weakness; early contractures (elbows, Achilles, neck extensors) | Contractures BEFORE weakness; cardiac conduction defects (sudden death risk) |
| Oculopharyngeal (OPMD) | PABPN1 / GCN trinucleotide expansion (polyalanine tract); normally 10 alanines, expanded 12–17 | AD | Onset >40 yrs; ptosis, dysphagia, proximal weakness | Late-onset ptosis + dysphagia; French-Canadian ancestry |
Board Pearl
Always screen for cardiac disease in DMD/BMD, DM1, Emery-Dreifuss, and LGMD with lamin A/C mutations. Cardiac conduction defects and cardiomyopathy are major causes of morbidity and mortality — sudden cardiac death can occur even when skeletal muscle weakness is mild.
Board Pearl
DM1 = distal weakness; DM2 = proximal weakness. DM1 shows anticipation (worsening severity in successive generations due to CTG repeat expansion). The congenital form of DM1 (inherited from the mother) presents with profound neonatal hypotonia and respiratory failure. DM2 has NO congenital form.
Dystrophin-Associated Glycoprotein (DAG) Complex
- Dystrophin → β-dystroglycan → α-dystroglycan → laminin-α2 (merosin) → ECM
- Sarcoglycans (α/β/γ/δ) form complex with dystroglycan
- Sarcoglycanopathies → LGMD R3-R6 (formerly LGMD2C-F)
- The DAG complex links the actin cytoskeleton through the sarcolemma to the extracellular matrix; disruption at any level causes muscular dystrophy
Periodic Paralyses and Channelopathies
Periodic Paralyses
| Disorder | Gene / Channel | Inheritance | Attack Features | Triggers / Treatment |
|---|---|---|---|---|
| Hypokalemic PP (HypoKPP) | CACNA1S (type 1, ~70%) or SCN4A (type 2) | AD | Long attacks (hours-days) | Carbs/exertion/insulin trigger; K+ replacement during attack; acetazolamide (sometimes worsens — beware in HypoKPP), dichlorphenamide |
| Hyperkalemic PP (HyperKPP) | SCN4A | AD | Short attacks (minutes-hours) | K+/cold/fasting trigger; thiazides, acetazolamide, dichlorphenamide |
| Andersen-Tawil syndrome | KCNJ2 (Kir2.1) | AD | Periodic paralysis + long QT (cardiac arrhythmia) + dysmorphism (small jaw, low-set ears, hypertelorism, fifth-finger clinodactyly) | Cardiology co-management; avoid QT-prolonging drugs |
| Paramyotonia congenita | SCN4A | AD | Cold-induced paradoxical myotonia (worsens with repeated exercise) | Avoid cold; mexiletine |
Board Pearl
Dichlorphenamide (Keveyis) — FDA-approved for BOTH hypo- and hyperKPP. Acetazolamide can paradoxically worsen HypoKPP in a subset of patients — especially those with SCN4A mutations.
Non-Dystrophic Myotonias
| Disorder | Gene / Channel | Inheritance | Key Features |
|---|---|---|---|
| Myotonia congenita (Thomsen) | CLCN1 (chloride channel) | AD | Mild; post-rest stiffness; warm-up phenomenon (improves with repeated activity) |
| Myotonia congenita (Becker) | CLCN1 (chloride channel) | AR | More severe; transient weakness with first contraction, then warm-up |
| Paramyotonia congenita | SCN4A (sodium channel) | AD | Cold-induced paradoxical myotonia (worsens with exercise) |
Board Pearl
First-line treatment for myotonia: mexiletine (Na channel blocker). Alternatives: ranolazine, lamotrigine, quinine (off-label). Thomsen warms up, Becker has transient weakness first then warms up, Paramyotonia worsens with cold and repeated exercise (paradoxical).
Inflammatory Myopathies
| Disorder | Immunopathology | Clinical / Antibody Features |
|---|---|---|
| Polymyositis (PM) | CD8+ T cells endomysial (cell-mediated); invade non-necrotic fibers expressing MHC-I | Proximal weakness; diagnosis of exclusion in modern era; overlap with IMNM |
| Dermatomyositis (DM) | CD4+ T + B cells perimysial (humoral, complement-mediated); MAC on endomysial capillaries → capillary dropout → perifascicular atrophy | Cutaneous (heliotrope, Gottron papules, shawl sign); anti-Jo-1 (antisynthetase), anti-Mi-2, anti-MDA5, anti-TIF1γ (cancer), anti-NXP-2 |
| Inclusion body myositis (IBM) | CD8 + rimmed vacuoles + amyloid/TDP-43/p62/tau | >50 yo, male predominant; quadriceps + finger flexor predominant; resistant to immunotherapy |
| Immune-mediated necrotizing myopathy (IMNM) | Minimal inflammation, prominent necrosis/regeneration | Anti-HMGCR (statin-associated, can persist after statin withdrawal; usually requires immunotherapy — IVIG is commonly important, with steroids and steroid-sparing agents tailored to severity/response; rituximab is an option, NOT universally required); anti-SRP (severe, dysphagia, cardiac) |
| Overlap / antisynthetase syndrome | Variable | Jo-1, PL-7, PL-12; mechanic's hands + ILD + arthritis + Raynaud |
Board Pearl
Treatment: prednisone + AZA/MMF/MTX; IVIG; rituximab for refractory cases. IVIG is FDA-approved for DM (2021 Octagam). Anti-TIF1γ in DM strongly associated with malignancy — screen for cancer.
Statin Myopathy Spectrum
- Asymptomatic CK elevation
- Myalgia (common, ~10%)
- Myositis (CK rise, weakness)
- Rhabdomyolysis (rare)
- Statin-IMNM (anti-HMGCR Ab): can persist after statin withdrawal; usually requires immunotherapy — IVIG is commonly important, with steroids and steroid-sparing agents tailored to severity/response; rituximab is an option, NOT universally required
Rhabdomyolysis
- CK >5× ULN (often >5000–10,000); tea-colored urine (myoglobinuria); AKI risk
- Treat aggressive IV fluids (target UOP 200–300 mL/h), manage hyperkalemia
- Causes: trauma, exertion (LDH ratio, McArdle, CPT2), statins, MDMA/cocaine, NMS, MH, serotonin syndrome, infection, genetic
Congenital Myopathies
| Disorder | Gene | Biopsy Hallmark | Clinical Features |
|---|---|---|---|
| Central core | RYR1 | Central cores (NADH-TR negative zones) | MH susceptibility; floppy infant, hip dislocation, scoliosis |
| Multiminicore | SEPN1 | Multiple small cores | Rigid spine, respiratory failure early |
| Nemaline | ACTA1, NEB, TPM2/3 | Rod bodies — Gomori trichrome red rods | Hypotonia, facial weakness, respiratory failure |
| Centronuclear / myotubular | X-linked MTM1 (severe); AD DNM2; AR BIN1 | Centrally placed nuclei | Severe neonatal hypotonia (X-linked) to adult-onset (AD) |
Board Pearl
All congenital myopathies are non-progressive or slowly progressive; biopsy diagnosis. Central core (RYR1) carries malignant hyperthermia risk — always inform anesthesiologist.
Muscle Biopsy Patterns
Key Biopsy Findings
| Biopsy Finding | Stain / Technique | Associated Condition | Significance |
|---|---|---|---|
| Ragged red fibers | Modified Gomori trichrome | Mitochondrial myopathies (MERRF, KSS, CPEO) | Subsarcolemmal accumulation of abnormal mitochondria |
| Rimmed vacuoles | H&E, modified Gomori trichrome | Inclusion body myositis (IBM) | Autophagic vacuoles with basophilic granular material; inclusions stain for amyloid (Congo red), TDP-43, p62, phospho-tau, ubiquitin — multi-protein aggregation; CD8 T cells endomysial; mixed myopathic+neurogenic EMG |
| Perifascicular atrophy | H&E | Dermatomyositis | Atrophy of fibers at the periphery of fascicles; MAC (C5b-9) deposition on endomysial capillaries (NOT perimysial); complement-mediated microangiopathy → perifascicular ischemic atrophy |
| Fiber type grouping | ATPase stain | Chronic reinnervation (any neuropathic process) | Clusters of same fiber type replacing normal checkerboard pattern; indicates collateral sprouting |
| Grouped atrophy | H&E, ATPase | Chronic denervation | Groups of small angular fibers from loss of a motor neuron |
| Target fibers | NADH-TR stain | Denervation / reinnervation | Three-zone pattern in cross-section; seen in neuropathic processes |
| Endomysial CD8+ T-cell invasion of non-necrotic fibers | Immunohistochemistry | Polymyositis, IBM | Cytotoxic T cells directly invading intact muscle fibers |
| Perivascular inflammation (B cells, CD4+) | Immunohistochemistry | Dermatomyositis | Complement-mediated microangiopathy → perifascicular ischemia |
| Necrotic fibers with macrophage invasion | H&E | Immune-mediated necrotizing myopathy (anti-SRP, anti-HMGCR) | Necrosis/regeneration with minimal lymphocytic inflammation |
| Nemaline rods | Modified Gomori trichrome | Nemaline myopathy (congenital) | Rod-shaped structures derived from Z-line material |
| Central cores | NADH-TR, oxidative stains | Central core disease (RYR1; less commonly CACNA1S) | Central zone lacking mitochondria and oxidative enzyme activity; associated with malignant hyperthermia risk |
💎 Board Pearl — Muscle Biopsy Finding → Disease (Quick Reference)
| Finding | Disease |
|---|---|
| Ragged red fibers (modified Gomori trichrome) | Mitochondrial myopathy |
| Rimmed vacuoles (with amyloid / TDP-43 / p62 / phospho-tau inclusions) | Inclusion body myositis (IBM) |
| Perifascicular atrophy (with MAC on endomysial capillaries) | Dermatomyositis (pathognomonic, even without skin findings) |
| Fiber type grouping (loss of normal mosaic pattern) | Chronic reinnervation (neurogenic process — e.g., MND, chronic neuropathy) |
| Central cores (NADH-TR) | Central core disease (RYR1; less commonly CACNA1S) — MH susceptibility |
| Nemaline rods (red on Gomori) | Nemaline myopathy (ACTA1, NEB) |
| Endomysial CD8 invasion of non-necrotic fibers | Polymyositis (or IBM) |
| Necrosis with minimal inflammation | Immune-mediated necrotizing myopathy (anti-HMGCR or anti-SRP) |
Clinical Pearl
Central core disease (RYR1 mutation) carries risk of malignant hyperthermia. Always ask about family history of anesthetic complications. Dantrolene is the treatment for malignant hyperthermia — it directly blocks the ryanodine receptor (RyR1).
Quick Reference
💎 10 Highest-Yield Muscle Physiology Facts for Boards
- A-band does NOT shorten during contraction (Always the same length); the I-band and H-zone shorten.
- Troponin C binds calcium → troponin I detaches from actin → tropomyosin moves → actin-myosin binding.
- ATP is required for relaxation (to detach myosin from actin) — this explains rigor mortis after ATP depletion.
- RyR1 mutation → malignant hyperthermia (also central core disease; CACNA1S less commonly).
- Type II fiber atrophy → steroid myopathy (also disuse, cachexia). CK normal.
- Henneman size principle — small (Type I, low-threshold) motor units are recruited first.
- McArdle disease (GSD V, myophosphorylase) → "second-wind" phenomenon; flat venous lactate on ischemic forearm exercise test.
- DMD = out-of-frame deletion (no dystrophin); BMD = in-frame deletion (truncated dystrophin) — reading-frame rule predicts severity.
- DM1 = distal weakness, frontal balding, cataracts (CTG repeat in DMPK); DM2 = proximal weakness (CCTG repeat in CNBP).
- IBM (>50 yo) = quadriceps + finger flexor weakness, rimmed vacuoles, multi-protein inclusions, mixed myopathic + neurogenic EMG, and POOR response to immunotherapy (distinguishes from PM/DM/IMNM).
Clinical Clue → Diagnosis
| Clinical Clue | Diagnosis |
|---|---|
| Boy + calf pseudohypertrophy + Gowers sign + CK >10,000 | Duchenne muscular dystrophy |
| Distal weakness + grip myotonia + cataracts + frontal balding | Myotonic dystrophy type 1 |
| Can’t whistle + scapular winging + asymmetric weakness | FSHD |
| Early contractures + cardiac conduction defects | Emery-Dreifuss |
| Exercise intolerance + "second wind" | McArdle disease |
| Recurrent rhabdomyolysis with fasting/prolonged exercise | CPT II deficiency |
| Adult + proximal weakness + diaphragm weakness out of proportion | Late-onset Pompe disease |
| Ptosis + ophthalmoplegia WITHOUT diplopia | CPEO (mitochondrial) |
| Elderly male + finger flexor + quad weakness + steroid-resistant | Inclusion body myositis |
| Heliotrope rash + Gottron papules + proximal weakness | Dermatomyositis |
| Sustained contraction + hyperthermia during anesthesia | Malignant hyperthermia (RyR1) |
| Proximal weakness + normal CK + on chronic steroids | Steroid myopathy |
Contraction Summary
| What Shortens | What Stays the Same |
|---|---|
| Sarcomere (Z-to-Z distance) | A-band (myosin length unchanged) |
| I-band (less actin-only zone) | Thick filament length |
| H-zone (less myosin-only zone) | Thin filament length |
Key Molecules to Remember
| Molecule | Role |
|---|---|
| Troponin C | Binds Ca²⁺ → initiates contraction |
| Tropomyosin | Blocks myosin-binding sites at rest |
| DHP receptor | Voltage sensor on T-tubule |
| RyR1 | Ca²⁺ release channel on SR; mutated in malignant hyperthermia |
| SERCA | Pumps Ca²⁺ back into SR → relaxation |
| Dystrophin | Links actin cytoskeleton to extracellular matrix; absent in DMD |
| Titin | Molecular spring; connects myosin to Z-line; provides passive elasticity |
References
- Aminoff MJ, Josephson SA. Aminoff's Neurology and General Medicine. 6th ed. Academic Press; 2021.
- Darras BT, Jones HR, Ryan MM, De Vivo DC. Neuromuscular Disorders of Infancy, Childhood, and Adolescence. 2nd ed. Academic Press; 2015.
- Engel AG, Franzini-Armstrong C. Myology. 3rd ed. McGraw-Hill; 2004.
- Katirji B, Kaminski HJ, Ruff RL. Neuromuscular Disorders in Clinical Practice. 2nd ed. Springer; 2014.
- Preston DC, Shapiro BE. Electromyography and Neuromuscular Disorders. 4th ed. Elsevier; 2021.
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor's Principles of Neurology. 12th ed. McGraw-Hill; 2023.
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