The muscle mitogen-activated protein kinase is altered in sporadic inclusion body myositis.
OBJECTIVE
To examine the origin of hyperphosphorylated proteins within the vacuolated myofibers in sporadic inclusion body myositis (s-IBM) and search for dysregulated intracellular protein phosphorylation.


BACKGROUND
s-IBM is morphologically characterized by primary endomysial inflammation and vacuolated myofibers containing tubulofilaments that originate from cytoskeletal proteins. Mitogen-activated protein kinases (MAPKs) play a role in regulating phosphorylation and maintaining the stability of the cytoskeletal architecture.


METHODS
Muscle biopsies from seven patients with s-IBM and 15 controls were examined for the expression of the active components of the various MAPKs, including p44/42MAPK, p38MAPK, p46JNK1, p54JNK2, and p54JNK3, using immunocytochemistry and Western blot analysis. The expression of selected phosphorylated components was also examined in the same specimens.


RESULTS
In s-IBM, but not the disease controls, the vacuolated muscle fibers express active p42MAPK but not JNK or p38MAPK. Western blots of cell lysates confirmed the hyperexpression of p42MAPK and demonstrated a novel 35 kD phosphoprotein. Antibodies against phosphoepitopes of the 35 kD protein preferentially immunostained antigens within the vacuolated muscle fibers of s-IBM but not disease controls.


CONCLUSIONS
In s-IBM, there is increased p42MAPK activation and abnormal intracellular protein phosphorylation with selective accumulation of a 35 kD phosphoprotein within the vacuolated fibers. Although the hyperexpression of 35kD protein may represent cytoskeletal by-products due to heightened p42MAPK activation, its abundant expression only in s-IBM implies that hyperphosphorylated myofibrillar proteins may be involved in the primary disease process.
Li
M
M
Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD 20892-1382, USA.
Dalakas
M C
MC
D000368:Aged; D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000201:enzymology* / Q000473:pathology; D016716:PC12 Cells / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D051381:Rats; D014617:Vacuoles / Q000378:metabolism
D003598:Cytoskeletal Proteins; D010768:Phosphoserine; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases