Inclusion Body Myositis Insights
June 1, 2000
Inclusion Body Myositis Insights
abstract & commentary
Source: Li M, Dalakas MC. The muscle mitogen-activated protein kinase is altered in sporadic inclusion body myositis. Neurology 2000;54:1665-1670.
Accumulations of amyloid-positive nonbranching filaments (termed tubulofilaments) and tau (hyperphosphorylated microtubule-associated protein, MAP) are among the pathologic hallmarks of sporadic inclusion body myositis (s-IBM). Are these the result of abnormal intracellular phosphorylation? Perhaps. Seven muscle biopsies from patients with s-IBM were compared to 15 control muscle biopsies, including inflammatory myositis (n = 7), vacuolar myopathy and denervation atrophy (n = 2 each), nonspecific myopathy (n = 1), and normals (n = 3) to determine if mitogen-activated protein kinase (MAPK) activity, crucial for cell surfaceto-cytoskeletal signal transduction, cytoskeletal architecture, and regulation of phosphorylation, was impaired.
Immunocytochemistry and Western blot analysis were used to assess the active components of MAPKs, including p44/42MAPK, p38MAPK, p46JNK1, p54JNK2, and p54JNK2. Vigorous expression of p44/42MAPK was present in and around vacuoles in s-IBM, but not in controls, whereas JNK and p38MAPK expression was weak in both. Western blot analysis confirmed these findings and further revealed a unique 35 kD phosphoserine-containing protein only in the s-IBM lysates. Abnormal intracellular phosphorylation and hyperphosphorylated myofibrillar proteins may be involved in the primary pathogenesis of s-IBM.
Commentary
Genetic susceptibility to s-IBM may also play a role in its pathogenesis (Askanas V, et al. Ann Neurol 2000;47:544-549). A 70-year-old man developed cardiac amyloidosis with congestive heart failure at age 63, followed, one year later, by progressive disabling proximal and distal limb muscle weakness, areflexia (except for decreased biceps reflex), normal sensory examination, and mild creatine kinase elevation (409 IU/L). Electrodiagnostic studies demonstrated a mixed axonal-demyelinating sensorimotor neuropathy with myopathic motor unit potentials. Typical s-IBM was seen on muscle biopsy with vacuolated muscle fibers (VMFs), mononuclear cell inflammation, intracellular plaque-like amyloid deposits, and beta-amyloid precursor protein in VMFs. Uniquely, muscle blood vessel congophilia was evident with transthyretin immunoreactivity in the vessel walls and VMFs. DNA analysis revealed homozygosity for the transthyretin Val122Ile allele (conversion of valine to isoleucine in the first base of codon 122), suggesting that this mutation may directly result in or predispose to the development of s-IBM. Alternatively the association may be incidental and noncausal in nature. —mr
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