Increased BACE1 mRNA and noncoding BACE1-antisense transcript in sporadic inclusion-body myositis muscle fibers-Possibly caused by endoplasmic reticulum stress

Sporadic inclusion-body myositis (s-IBM) is the most common muscle disease of older persons. Its muscle-fiber phenotype shares several molecular similarities with Alzheimer-disease (AD) brain, including increased A beta PP, accumulation of amyloid-beta (A beta), and increased BACE1 protein. A beta 42 is prominently increased in AD brain and within s-IBM fibers, and its oligomers are putatively toxic to both tissues accordingly, minimizing A beta 42 production can be a therapeutic objective in both tissues. The pathogenic development of s-IBM is unknown, including the mechanisms of BACE1 protein increase. BACE1 is an enzyme essential for production from A beta PP of A beta 42 and A beta 40, which are proposed to be detrimental within s-IBM muscle fibers. Novel noncoding BACE1-antisense (BACE1-AS) was recently shown (a) to be increased in AD brain, and (b) to increase BACE1 mRNA and BACE1 protein. We studied BACE1-AS and BACE1 transcripts by real-time PCR (a) in 10 s-IBM and 10 age-matched normal muscle biopsies; and (b) in our established ER-Stress-Human-Muscle-Culture-IBM Model, in which we previously demonstrated increased BACE1 protein. Our study demonstrated for the first time that (a) in s-IBM biopsies BACE1-AS and BACE1 transcripts were significantly increased, suggesting that their increased expression can be responsible for the increase of BACE1 protein; and (b) experimental induction of ER stress significantly increased both BACE1-AS and BACE1 transcripts, suggesting that ER stress can participate in their induction in s-IBM muscle. Accordingly, decreasing BACE1 through a targeted downregulation of its regulatory BACE1-AS, or reducing ER stress, might be therapeutic strategies in s-IBM, assuming that it would not impair any normal cellular functions of BACE1. (C) 2010 Elsevier Ireland Ltd. All rights reserved.