Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027121 (myositis)
 4,538 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sporadic inclusion-body myositis (IBM) is the most common, progressive muscle disease of older individuals. We investigated the presence of BACE1 and BACE2-two beta secretases that cleave amyloid-beta-precursor protein-in muscle-biopsy samples from patients with IBM and from controls. On immunofluorescence, BACE1 and BACE2 co-localised with amyloid beta in IBM vacuolated muscle fibres, but were not found in controls. Immunoblotting showed increased BACE2 but not BACE1 in patients with IBM compared with controls. Our study suggests that both of these proteases might participate in processing of amyloid-beta-precursor protein in IBM muscle fibres.
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PMID:Presence of BACE1 and BACE2 in muscle fibres of patients with sporadic inclusion-body myositis. 1174 23

BACE1 and BACE2 are recently discovered enzymes participating in processing of amyloid beta precursor protein (AbetaPP). Their discovery is contributing importantly to understanding the mechanism of amyloid-beta generation, and hence the pathogenesis of Alzheimer's disease (AD). Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy (h-IBM) are progressive muscle diseases in which overproduction of AbetaPP and accumulation of its presumably toxic proteolytic product amyloid-beta (Abeta) in abnormal muscle fibers appear to play an important upstream role in the pathogenic cascade. In normal human muscle AbetaPP was also shown to be present and presumably playing a role (a) at neuromuscular junctions and (b) during muscle development. To investigate whether BACE1 and BACE2 play a role in normal and diseased human muscle, we have now studied them by immunocytochemistry and immunoblotting in 35 human muscle biopsies, including: 5 s-IBM; 5 chromosome-9p1-linked quadriceps-sparing h-IBM; and 25 control muscle biopsies. In addition, expression of BACE1 and BACE2 was studied in normal cultured human muscle. Our studies demonstrate that BACE1 and BACE2 (a) are expressed in normal adult muscle at the postsynaptic domain of neuromuscular junctions, and in cultured human muscle; (b) are accumulated in the form of plaque-like inclusions in both s-IBM and h-IBM vacuolated muscle fibers; and (c) are immunoreactive in necrotizing muscle fibers. Accordingly, BACE1 and BACE2 participate in normal and abnormal processes of human muscle, suggesting that their functions are broader than previously thought.
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PMID:BACE1 and BACE2 in pathologic and normal human muscle. 1261 21

Increased amyloid-beta precursor protein (A beta PP) and amyloid-beta (A beta) accumulation appear to be upstream steps in the pathogenesis of sporadic inclusion-body myositis (s-IBM). BACE1, participating in A beta production is also increased in s-IBM muscle fibers. Nogo-B and Nogo-A belong to a family of integral membrane reticulons, and Nogo-B binding to BACE1 blocks BACE1 access to A beta PP, decreasing A beta production. We studied Nogo-B and Nogo-A in s-IBM muscle and in our IBM muscle culture models, based on A beta PP-overexpression or ER-stress-induction in cultured human muscle fibers (CHMFs). We report that: (1) in biopsied s-IBM fibers, Nogo-B is increased, accumulates in aggregates, is immuno-co-localized with BACE1, and binds to BACE1; Nogo-A is undetectable. (2) In CHMFs, (a) A beta PP overexpression increases Nogo-B, Nogo-A, and BACE1, (b) ER stress increases BACE1 but decreases Nogo-B and Nogo-A, (c) Nogo-B and Nogo-A associate with BACE1. Accordingly, two novel mechanisms, A beta PP overexpression and ER stress, are involved in Nogo-B and Nogo-A expression in human muscle. We propose that in s-IBM muscle the Nogo-B increase may represent an attempt by muscle fiber to decrease A beta production. However, the increase of Nogo-B seems insufficient because A beta continues to accumulate and the disease progresses. We propose that manipulations, which increase Nogo-B in s-IBM muscle might offer a new therapeutic opportunity.
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PMID:NOGO is increased and binds to BACE1 in sporadic inclusion-body myositis and in A beta PP-overexpressing cultured human muscle fibers. 1776 14

BACE2 is a protease homologous to BACE1 protein, an enzyme involved in the amyloid formation of Alzheimer disease (AD). However, despite the high homology between these two proteins, the biological role of BACE2 is still controversial, even though a few studies have suggested a pathogenetic role in sporadic inclusion-body myositis and hereditary inclusion-body myopathy, which are characterized by vacuolization of muscular fibers with intracellular deposits of proteins similar to those found in the brain of AD patients. Although BACE2 has also been identified in the pancreas, its function remains unknown and its specific localization in different pancreatic cell types has not been definitively ascertained. For these reasons, the authors have investigated the cellular and subcellular localization of BACE2 in normal rodent pancreases. BACE2 immunoreactivity was found in secretory granules of beta cells, co-stored with insulin and IAPP, while it was lacking in the other endocrine and exocrine cell types. The presence of BACE2 in secretory granules of beta cells suggests that it may play a role in diabetes-associated amyloidogenesis.
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PMID:BACE2 is stored in secretory granules of mouse and rat pancreatic beta cells. 1911 66

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.
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PMID:Increased BACE1 mRNA and noncoding BACE1-antisense transcript in sporadic inclusion-body myositis muscle fibers--possibly caused by endoplasmic reticulum stress. 2023 12