Inclusion-body myositis: muscle-fiber molecular pathology and possible pathogenic significance of its similarity to Alzheimer's and Parkinson's disease brains

Abstract

Sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause and lacks successful treatment. Here we summarize diagnostic criteria and discuss our current understanding of the steps in the pathogenic cascade. While it is agreed that both degeneration and mononuclear-cell inflammation are components of the s-IBM pathology, how each relates to the pathogenesis remains unsettled. We suggest that the intra-muscle-fiber degenerative component plays the primary role, leading to muscle-fiber destruction and clinical weakness, since anti-inflammatory treatments are not of sustained benefit. We discuss possible treatment strategies aimed toward ameliorating a degenerative component, for example, lithium and resveratrol. Also discussed are the intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's diseases, the most common neurodegenerative diseases associated with aging. Similarities include, in the respective tissues, cellular aging, mitochondrial abnormalities, oxidative and endoplasmic-reticulum stresses, proteasome inhibition and multiprotein aggregates.

Fig. 1. Light-microscopic diagnostic features of the s-IBM muscle biopsy

a,b - Engel Trichrome staining demonstrating vacuolated and atrophic muscle fibers, and mononuclear-cell inflammation. c - Congo-red staining, visualized through Texas-red filters and epifluorescence illumination, shows various-sized amyloid deposits within two abnormal muscle fibers. d - Diagnostic inclusionswithin muscle fibers identified by staining with SMI-31 antibody, which identifies phosphorylated tau. e - Typical muscle-fiber inclusions identified with anti-ubiquitin antibody. f - Various-sized amyloid-β immunoreactive inclusions within a muscle fiber. a,b ×1250; c-f ×2100.

Fig. 2. Characteristic electronmicroscopic abnormalities of s-IBM muscle fibers

a, b - Several paired helical filaments (PHFs), in transmission electronmicroscopy. c - Cluster of PHFs immuno-stained with AT8 antibody, which recognizes phosphorylated tau, and processed for horseradishimmunoperoxidase staining demonstrates dark reaction-product covering PHFs exclusively, while the adjacent portion of the myofiber is not immunostained. d - Cluster of PHFs immuno-stained with SMI-31 antibody, which recognizes phosphorylated tau, and processed for gold-imuno-electronmicroscopy; this demonstrates that gold particles associate only with PHFs, while the adjacent portion of the myofiber is not immunostained. e, f - Gold-immuno-electronmicroscopy of Aβ illustrates its localization on amorphous and floccular material, and on thin 6-10nm amyloid-like fibrils (arrows). a,b,e,f × 120,000; c,d × 60,000.

Fig. 3. Amyloid-β 42 (Aβ42) and Congo-red positivities in s-IBM muscle fibers

a - imunofluorescence and c - gold-immuno-electronmicroscopy of Aβ42 -- stained with an antibody specifically recognizing Aβ42 (ref.97 here) - -- illustrate that Aβ42 aggregates in a correspond to 6-10 nm amyloid-like filaments in c. b - Cong-red staining of a transverse parallel, but not closely adjacent, section of the same fiber as in (a), demonstrating several amyloid inclusions. a, b ×2100; c ×2100.

Fig. 4. Proposed pathologic regulation of myostatin-precursor protein (MSTN-PP)/ myostatin (MSTN) in s-IBM muscle fibers

Endoplasmic reticulum (ER) stress induces MSNT-PP transcription through activation of NF-κB. Increased MSTN then leads to muscle fiber atrophy. Furthermore, increased AβPP/Aβ, which also causes proteasome inhibition, binds to MSTN-PP/MSTN and both accumulate in the form of probably-insoluble aggregates.

Fig. 5. Proposed adverse effects of decreased SIRT1 deacetylase activity in s-IBM muscle fibers

Decreased deacetylase activity of SIRT1 activates NF-κB by increasing its acetylation (NF-κB-Ac). This leads to increased myostatin, and other detrimental consequences. Decreased SIRT1 activity also increases AβPP and Aβ, resulting in their known detrimental effects in s-IBM muscle fibers, as detailed in the text. Decreased SIRT1 activity might also inhibit autophagy, contributing to the accumulation of multiprotein aggregates.