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

Abstract

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 AbetaPP, accumulation of amyloid-beta (Abeta), and increased BACE1 protein. Abeta42 is prominently increased in AD brain and within s-IBM fibers, and its oligomers are putatively toxic to both tissues--accordingly, minimizing Abeta42 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 AbetaPP of Abeta42 and Abeta40, 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.

Figure1

BACE1 and BACE1-AS transcripts in control muscle biopsies (A), and in control non-treated normal cultured human muscle fibers (B). In both systems, BACE1-AS transcript is much less abundant than BACE1 transcript. Data are presented as mean ± SEM.

Figure2

BACE1 and BACE1-AS transcripts in biopsied control “C” and s-IBM muscle fibers. BACE1 and BACE1-AS transcripts are significantly increased in s-IBM as compared to controls. Data are presented as mean ± SEM.

Figure3

BACE1 and BACE1-AS transcripts in cultured human muscle fibers: “C” = non-treated controls. Tm = Tunicamycin, Tg = Thapsigargin. Under ER stress conditions induced by either Tm or Tg, BACE1 and BACE1-AS transcripts are significantly increased. Data are presented as mean ± SEM.