MUSCLE FIBER NECROSIS

General features

• Necrosis: Cellular changes
  • Cytoplasmic swelling (oncosis)
  • Rupture of plasma membrane
  • Cytoplasmic organelles: Swelling; Loss
  • Chromatin: Condensation, moderate
  • Absent: Apoptotic & Autophagic markers
• Necrosis in muscle
  • Associated with break in, or loss of, muscle surface fiber membrane
  • Results in: Irreversible damage to whole, or segment of, muscle fiber
  • All organelles involved
• Necrotic muscle fibers: Morphology
  • Earliest changes: Sarcolemma & Cytoplasm
  • H & E and GT
    • Pale cytoplasm staining
    • Intermyofibrillar network: Absent
  • NADH: Pale or absent staining
  • Mitochondrial: Pale or absent staining
  • Myosin ATPase: Pale or absent staining
  • Markers of necrotic muscle fiber necrosis
    • Cytoplasm of necrotic muscle fibers
      • C_5b-9 Complement (Memebrane attack complex (MAC))
      • IgM
      • Ca⁺⁺: Increased in necrotic muscle fibers
    • Around the rim of necrotic muscle fibers: Alkaline phosphatase
  • Ultrastructure
    • Loss of plasma membrane
    • Myofibrils: Lysed or Lost
    • Mitochondria: Abnormal
    • Late: Granular or filamentous debris in fibers
  • Rare in intrafusil muscle fibers
• Associated cellular alterations
  • No common biochemical denominator
  • Mitochondrial
    • Uncoupling
    • Production of reactive oxygen species (ROS)
    • Mitochondrial membrane permeabilization: Often controlled by cyclophilin D
    • Ca⁺⁺ overload
  • Lysosomal
    • ROS production by Fenton reactions
    • Membrane permeabilization
  • Nuclear
  • Hyperactivation of PARP-1
  • Hydrolysis of NAD⁺
  • Lipid degradation
    • Activation of phospholipases, lipoxygenases & sphingomyelinases
  • Ca⁺⁺
    • Activation of non-caspase proteases: Calpains; Cathepsins
• Necrosis variant: Regulated necrosis (Necroptosis)
  • Stimuli
    • Death domain receptors: TNFR1 , Fas/CD95 , TRAIL-R
    • Toll-like receptors: TLR3 , TLR4
  • Pathway: Kinase RIP1 (RIPK1)
• Necrosis in muscle: Follow-up processes
  • Clean-up of necrotic muscle fibers
    • Proliferation or Migration of Phagocytic cells
    • Attraction of Phagocytic cells to necrotic muscle fiber
    • Phagocytosis of necrotic muscle fibers
  • Cellular proliferation
    • Muscle: Formation of regenerating muscle fibers
    • Connective tissue & Fat

Muscle Fiber Necrosis: Morphology

H & E Stain	Normal muscle fiber
	Necrotic muscle fiber: Pale
	Necrotic muscle fiber:   Phagocytosis by macrophages
	Hypercontracted necrotic muscle fiber
	Perimysium

H&E	Esterase stain
Necrotic muscle fiber, Early (left) Fiber is pale & enlarged. Internal nuclei may reflect invasion by macrophages.	Necrotic muscle fiber, Late Fiber is invaded by macrophages.

Toluidine blue stain Longitudinal section: Pale necrotic muscle fiber invaded by cells
Toluidine blue stain Cross-section: Pale necrotic muscle fiber invaded by cells	Toluidine blue stain Necrotic muscle fiber

Toluidine blue stain Cells in necrotic fiber

Toluidine blue stain Non-necrotic muscle fiber: Dilated SR (Left)

Necrotic muscle fibers: Complement C5b-9 (MAC) deposition

Stain: C5b-9 components of complement (Membrane attack complex (MAC)) Necrosis: C5b-9 deposition diffusely within muscle fibers