PONM17 Augmentation of the heat shock response in an in vitro model of sporadic inclusion body myositis

Abstract

Sporadic inclusion body myositis (IBM), the commonest myopathy acquired by those aged over 50 years, remains without proven treatment. We developed an in vitro disease model, using primary satellite cells, in which overexpression of βAmyloid Precursor Protein or exposure to inflammatory mediators IL1β/TNF-α reproduced salient features of the cellular environment in IBM. With a view to screening pharmaceutical agents, we investigated potential outcome measures relevant to IBM pathology, particularly those where inflammatory and degenerative processes may interact. Using fluorescent imaging, elevated basal cytosolic calcium and disturbed ER calcium handling was demonstrated in myogenic cells overexpressing APP or exposed to IL1β/TNF-α. These potentially pathological disturbances were significantly improved by treatment with arimoclomol, a co-inducer of the cytoprotective heat shock response (HSR). Cytoplasmic redistribution of TAR DNA binding protein (TDP43) from the nucleus is a fundamental feature of IBM tissue. Overexpression of APP and exposure to the inflammatory mediators reproduced this effect in vitro. These degenerative and inflammatory stimuli also triggered nuclear translocation of NfkB, reflecting its activation, a potential mechanism by which pathological processes are sustained in IBM. Redistribution of TDP43 and NFkB was significantly attenuated by Arimoclomol treatment. These data support further investigation of HSR augmentation as a therapeutic strategy in IBM.