Beta-Amyloid is a Substrate of Autophagy in Sporadic Inclusion Body Mysositis

Sporadic Inclusion Body Myositis (sIBM) is the most common acquired muscle disease in patients above 50 years of age. Apart from inflammation in the skeletal muscle, overexpression of amyloid precursor protein (APP) and intracellular accumulation of its proteolytic fragment beta-amyloid play a central role in the pathogenesis of sIBM.

We demonstrate here that the essential autophagy protein Atg8/LC3, which associates with preautophagosomal and autophagosomal membranes via lipidation, colocalizes with APP in cultured human muscle cells. In addition, APP/beta-amyloid-containing autophagosomes can be observed at increased frequency in muscle fibers of sIBM muscle biopsies, but not in non-myopathic muscle or non-vacuolated myopathic controls. APP/beta-amyloid and Atg8/LC3 double-positive compartments were almost exclusively observed in degenerating muscle fibers of the type II (fast-twitching) and were in part associated with overexpression of major histocompatibility complex (MHC) class I and II on myofibers and invasion by CD4+ and CD8+ T cells. Treatment with proinflammatory cytokines further induced autophagic degradation in human muscle cells in vitro.

These findings indicate that APP/beta-amyloid is a substrate for autophagy in skeletal muscle and suggest that degradation of aggregate-prone proteins via macroautophagy can be linked with both immune-mediated and degenerative tissue damage in sIBM. A better understanding of this pathway in skeletal muscle and in the inflammatory environment of sIBM might provide a rationale for novel therapeutic strategies targeting pathogenic protein aggregation.