Skeletal Muscle Pathology

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Motor unit=

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AHC + all the muscle fibers it innervates.

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-xs of normal skeletal m.
-multinucleated; MOST nuclei peripheral

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Organization of a sarcomere?

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sarcomere on EM

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Contrast type 1 and 2 m fibers:

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Type 1:
Red (dark meat)
Slow twitch
Sustained action
Oxidative enzymes (NADH)
More mitochondria
More fat
Oxidative phosphorylation

Type 2:
White (meat)
Fast twitch
Rapid action
Glycolytic enzymes (phosphorylase)
Fewer mitochondria
Less fat
Glycolysis

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Different composition of muscle in different people

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ATPase stain of m.
-type 2 fibers are dark
-type 1 fibers are light
-they are intermixed with each other in normal muscle.

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A: ATPase histochemical staining, at pH 9.4, of normal muscle showing checkerboard distribution of intermingled type 1 (light) and type 2 (dark) fibers.

B: in contrast, fibers of either histochemical type are grouped together after reinnervation of muscle. This is not normal muscle!

C: A cluster of atrophic fibers (group atrophy) in the center (arrow). In neurogenic disease.

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Muscle Atrophy:

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*Nonspecific response to a variety of skeletal muscle disorders, myopathies, and dystrophies
*Abnormally small myofibers
*Specific types of atrophy
-Neurogenic atrophy
-Type 2 fiber atrophy
+Corticosteroid myopathy
+Disuse myopathy

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-Early denervation.
-typically involves early type 2 selective atrophy

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-Individual fiber atrophy (early denervation)
-typically involves early type 2 selective atrophy

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-Fiber type grouping
-Leading to grouped atrophy

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Grouped atrophy

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-Re-innervation- Type grouping- ATPase
-indicative of some kind of neurogenic disease.

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-Type 2 Fiber Atrophy
-from chronic steroid use or disuse of muscle.

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Dystrophy vs. congenital myopathy:

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Dystrophy:
A degenerative disorder with destruction of muscles
Progressive weakness
Develops after birth

Congenital Myopathy:
A fixed dysfunction of muscle
Nonprogressive muscle weakness
Present at birth

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Duchenne Muscular Dystrophy:

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*X-linked (boys)
*Onset at age 5-6: children walk but never run
*Proximal muscle weakness
*Pseudohypertrophy of calves
*Greatly elevated creatine phosphokinase (CPK)
*Wheelchair-bound in early teens
*Death in late teens

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inheritance vs. de novo mutation in DMD:

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L: Pseudohypertrophy of the the calves
R: Lumbar Lordosis

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How do kids stand up in DMD?

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-Gower's sign
-Due to proximal m weakness

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Becker Muscular Dystrophy

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-X-linked
-Due to dystrophin mutation
-Later onset (2-16 years) than DMD
-Milder clinical course than DMD
-Long survival (middle age)

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Becker Muscular Dystrophy

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*DMD; you can see this with any muscular dystrophy
*Necrotic fibers with macrophages, fatty replacement of muscle, fibrosis, fiber size variability

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Role of dystrophin in muscle?

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-Acts as a stabilizing bridge

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Limb-Girdle Muscular Dystrophy

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*A grouping of mutations
*Proximal muscle weakness
*Autosomal dominant or recessive
*Mutations in cytoskeletal proteins (e.g. sarcoglycans, caveolin)

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What kind of mutations do you see in Limb-Girdle Muscular Dystrophy?

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A mutation in any of these!

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Myotonic Muscular Dystrophy- Clinical Features:

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*Onset at age 20-30
*DISTAL weakness
*Myotonia—cannot relax contracted muscle
*Hatchet-like face (atrophy of masseters)
*Frontal baldness
*Cataracts, cardiac conduction abnormalities, endocrine abnormalities
*Progress is slow, sometimes spanning 50 to 60 years

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Myotonic dystrophy

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Myotonic Muscular Dystrophy- Genetic traits:

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*Autosomal dominant inheritance
*Chromosome 19q.13.3 –
*Trinucleotide repeat (CTG)
*Genetic anticipation
*Codes for myosin protein kinase
*Congenital form is always inherited from mother

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Myotonic Muscular Dystrophy-Pathologic Features:

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Large numbers of central nuclei
Striated annulets (ring fibers)
Selective atrophy of type I fibers

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-Myotonic Muscular Dystrophy
-Central nuclei and ring fiber
*Large numbers of central nuclei
*Striated annulets (ring fibers)
*Selective atrophy of type I fibers

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Less common inherited myopathies:

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*“Congenital” (e.g. central core disease +/- malignant hyperthermia)
*“Channelopathies” (ion channel myopathies)
-Myotonia congenita
-Periodic paralyses
*Inborn errors of metabolism
-Glycogen-storage myopathies
-Lipid-storage myopathies
*Mitochondrial myopathies

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Mitochondrial Myopathies:

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*Muscle

*Extraocular muscles
-Progressive external ophthalmoplegia
-(Kearns-Sayre syndrome)

*Brain
-MELAS
-MERRF

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traits of mito DNA:

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-Has a different genetic code from nuclear DNA
-Is more tightly packed (no introns)
-Mutates at a higher rate
-Has less efficient repair mechanisms
-Is present in hundreds of thousands of copies in every cell
-Is maternally inherited

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A: Mitochondrial myopathy showing an irregular fiber with subsarcolemmal collections of mitochondria that stain red with the modified Gomori trichrome stain (ragged red fiber).

B: Electron micrograph of mitochondria from biopsy specimen in A showing "parking lot" inclusions (arrowheads).

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Ragged red fiber (trichrome stain)
-think MITOchondrial problem

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Paracrystalline (parking lot) inclusions in mitochondria (EM)

-think mitochondrial myopathy

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Acquired Myopathies:

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*Toxic
-Intrinsic (e.g. thyrotoxic myopathy)
-Extrinsic (e.g. alcohol, chloroquine, STATINS)

*Inflammatory
-Polymyositis
-Dermatomyositis
-Inclusion body myositis

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polymyositis

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Dermatomyositis

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Polymyositis vs. Dermatomyositis:

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*Polymyositis (L)
CD8+ T-cells
Direct fiber damage
Inflammation around fibers
Not antibody mediated

*Dermatomyositis (R)
B cells/CD4+ T-cells
Ischemic fiber damage
Inflammation around blood vessels
Perifascicular atrophy
Membrane-attack complex

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Invasion of intact fiber by lymphocytes- polymyositis

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-Interstitial inflammation-polymyositis
-inflammatory cells completely surrounding the fiber

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Necrotic muscle fiber (myophagocytosis) in polymyositis (trichrome stain)

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Skin rash- dermatomyositis
-don't ALWAYS see this

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Vascular inflammation-dermatomyositis

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Focal muscle damage- dermatomyositis

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Perifascicular Atrophy--Dermatomyositis
-due to decreased blood flow; an ischemic watershed phenomenon

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Inclusion Body Myositis:

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*15-20% of inflammatory myopathies
*Patients older than 50
*M/F: 3/1
*Distal (upper limb), as well as proximal (lower) weakness
*Myopathic and neurogenic features on EMG
*CPK only mildly elevated
*Lack of response to treatment

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Inclusion Body Myositis- Histologic Features:

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*Modest inflammation
*Groups of atrophic fibers (correlation with neurogenic features on EMG)
*Rimmed vacuoles!!! hallmark
*Intranuclear virus-like particles on EM (difficult to find)
*Inclusion bodies: staining for ubiquitin, amyloid, and amyloid precursor protein

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Rimmed vacuoles in Inclusion Body Myositis

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Inclusion bodies stained for beta-amyloid in Inclusion Body Myositis

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-Ultrastructure: Vacuoles contain tubulovesicular material
-EM correlate of inclusion bodies in Inclusion Body Myositis

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Filamentous intranuclear inclusion (low mag)
-in Inclusion Body Myositis

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Filamentous intranuclear inclusion (high mag) in Inclusion Body Myositis

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Neuromuscular Junction disorders:

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*Myasthenia gravis
Increasing weakness with repetitive action
Antibodies to acetylcholine receptor
May be associated with thymoma

*Lambert-Eaton myasthenic syndrome
Increasing strength with repetitive action
Antibodies to presynaptic calcium channels
Frequently a paraneoplastic (lung SCC) syndrome

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Rhabdomyosarcoma:

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*Most common soft tissue sarcoma of childhood and adolescence
*Frequently in head/neck and GU regions
*Associated with t(2;13) translocation: dysregulation of muscle differentiation by mutant protein

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Rhabdomyosarcoma: The rhabdomyoblasts are large and round and have abundant eosinophilic cytoplasm; no cross-striations are evident here.

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Rhabdomyosarcoma- diagnosis, treatment, and prognosis:

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*Diagnosis
Sarcomeres on electron microscopy
Immunohistochemistry
Muscle-specific actin
DESMIN

*Treatment: surgery, XRT, chemotherapy

*Prognosis: potentially curable in 2/3 of children; adults do much worse