IL-1 beta-Induced Accumulation of Amyloid: Macroautophagy in Skeletal Muscle Depends on ERK

Abstract

The pathology of inclusion body myositis (IBM) involves an inflammatory response and beta-amyloid deposits in muscle fibres. It is believed that MAP kinases such as the ERK signalling pathway mediate the inflammatory signalling in cells. Further, there is evidence that autophagic activity plays a crucial role in the pathogenesis of IBM. Using a well established in vitro model of IBM, the autophagic pathway, MAP kinases, and accumulation of beta-amyloid were examined. We demonstrate that stimulation of muscle cells with IL-1 beta and IFN-gamma led to an increased phosphorylation of ERK. The ERK inhibitor PD98059 diminished the expression of proinflammatory markers as well as the accumulation of beta-amyloid. In addition, IL-1 beta and IFN-gamma led to an increase of autophagic activity, upregulation of APP, and subsequent accumulation of beta-sheet aggregates. Taken together, the data demonstrate that the ERK pathway contributes to formation of beta-amyloid and regulation of autophagic activity in muscle cells exposed to proinflammatory cell stress. This suggests that ERK serves as an important mediator between inflammatory mechanisms and protein deposition in skeletal muscle and is a crucial element of the pathology of IBM.