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The muscle mitogen-activated protein kinase is altered in sporadic inclusion body myositis

From the Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD.

Address correspondence and reprint requests to Dr. Marinos C. Dalakas, Chief—Neuromuscular Diseases Section, NINDS, NIH, Building 10, Room 4N248, 10 Center Drive, MSC 1382, Bethesda, MD 20892-1382.

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.

CONCLUSION: 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.

Key words: Muscle mitogen-activated protein kinase—Sporadic inclusion body myositis.

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