Pathogenesis Of Sporadic Inclusion Body Myositis Research Articles

Pathogenic Considerations in Sporadic Inclusion-Body Myositis, a Degenerative Muscle Disease Associated With Aging and Abnormalities of Myoproteostasis

The pathogenesis of sporadic inclusion-body myositis (s-IBM) is complex; it involves multidimensional pathways and the most critical issues are still unresolved. The onset of muscle fiber damage is age related and the disease is slowly, but inexorably, progressive. Muscle fiber degeneration and mononuclear cell inflammation are major components of s-IBM pathology, but which is precedent and how they interrelate is not known. There is growing evidence that aging of the muscle fiber associated with intramyofiber accumulation of conformationally modified proteins plays a primary pathogenic role leading to muscle fiber destruction. Here, we review the presumably most important known molecular abnormalities that occur in s-IBM myofibers and that likely contribute to s-IBM pathogenesis. Abnormal accumulation within the fibers of multiprotein aggregates (several of which are congophilic and, therefore, generically called "amyloid") may result from increased transcription of several proteins, their abnormal posttranslational modifications and misfolding, and inadequate protein disposal, that is, abnormal "myoproteostasis," which is combined with and may be provoked or abetted by an aging intracellular milieu. The potential cytotoxicity of accumulated amyloid β protein (Aβ42) and its oligomers, phosphorylated tau in the form of paired helical filaments and α-synuclein, and the putative pathogenic role and cause of the mitochondrial abnormalities and oxidative stress are reviewed. On the basis of our experimental evidence, potential interventions in the complex, interwoven pathogenic cascade of s-IBM are suggested.

Sporadic inclusion-body myositis: Conformational multifactorial ageing-related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid-β42 oligomers and phosphorylated tau

The pathogenesis of sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is complex and multifactorial. Both the muscle fiber degeneration and the mononuclear-cell inflammation are components of the s-IBM pathology, but how each relates to the pathogenesis remains unsettled. We consider that the intramuscle fiber degenerative component plays the primary and the major pathogenic role leading to muscle fiber destruction and clinical weakness. In this article we review the newest research advances that provide a better understanding of the s-IBM pathogenesis. Cellular abnormalities occurring in s-IBM muscle fibers are discussed, including: several proteins that are accumulated in the form of aggregates within muscle fibers, including amyloid-β42 and its oligomers, and phosphorylated tau in the form of paired helical filaments, and we consider their putative detrimental influence; cellular mechanisms leading to protein misfolding and aggregation, including evidence of their inadequate disposal; pathogenic importance of endoplasmic reticulum stress and the unfolded protein response demonstrated in s-IBM muscle fibers; and decreased deacetylase activity of SIRT1. All these factors are combined with, and perhaps provoked by, an ageing intracellular milieu. Also discussed are the intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's disease patients, the two most common neurodegenerative diseases associated with ageing. Muscle biopsy diagnostic criteria are also described and illustrated.

Expanded T cell receptor Vβ–restricted T cells from patients with sporadic inclusion body myositis are proinflammatory and cytotoxic CD28null T cells

Sporadic inclusion body myositis (IBM) is characterized by T cell infiltrates in muscle tissue, but their functional role is unclear. Systemic signs of inflammation are lacking, and the absence of beneficial effects following immunosuppression has challenged the notion of a role for the immune system. This study was undertaken to investigate the phenotype and functionality of T cells, specifically a subset of proinflammatory, cytotoxic, and apoptosis-resistant T cells defined as CD28(null) T cells, in the pathogenesis of sporadic IBM. A cohort of 27 patients with sporadic IBM was analyzed for the frequency of circulating and muscle-infiltrating CD28(null) T cells. The T cell receptor (TCR) V(β) usage was determined using flow cytometry and immunohistochemistry. Anti-CD3-stimulated peripheral blood mononuclear cells were analyzed for intracellular interferon-γ and cytotoxic potential by flow cytometry. We found striking accumulations of both CD8+CD28(null) and CD4+CD28(null) T cells, which represented the TCR V(β) -expanded T cells in sporadic IBM. Such CD28(null) T cells were abundant both in the inflamed muscle tissue and in the circulation. Although the specific TCR V(β) expansions varied between patients, both CD8+CD28(null) and CD4+CD28(null) T cells consistently displayed a highly proinflammatory and cytotoxic potential. Our results suggest that CD28null T cell expansions represent the previously described expanded T cell subsets in sporadic IBM, and their proinflammatory capacity and presence in both muscle tissue and the circulation may imply a role of immune activation in sporadic IBM. In addition, CD4+CD28(null) T cells may exert cytotoxic effects directly on muscle fibers due to a cytotoxic potential similar to that in CD8+ T cells.

Increased aging in primary muscle cultures of sporadic inclusion-body myositis

Ageing is thought to participate to the pathogenesis of sporadic inclusion-body myositis (s-IBM). Although the regenerative potential of s-IBM muscle is reduced in vivo, age-related abnormalities of satellite cells possibly accounting for the decline of muscle repair have not been demonstrated. Here we show that proliferation rate and clonogenicity of s-IBM myoblasts are significantly lower and doubling time is longer than normal age-matched controls, indicating that proliferative capacity of s-IBM muscles becomes exhausted earlier. Telomere shortening is detected in s-IBM cells suggesting premature senescence. Differently from controls, s-IBM myoblasts show increased active beta-catenin mainly localized within myonuclei, indicating active Wnt stimulation. After many rounds of muscle growth, only s-IBM myoblasts accumulate congophilic inclusions and immunoreactive Abeta(1-40) deposits. Therefore, s-IBM myoblasts seem to have a constitutively impaired regenerative capacity and the intrinsic property, upon sufficient aging in vitro, to accumulate Abeta. Our results might be valuable in understanding molecular mechanisms associated with muscle aging underlying the defective regeneration of s-IBM muscle and provide new clues for future therapeutic strategies.

Inclusion-body myositis, a multifactorial muscle disease associated with aging: current concepts of pathogenesis

Sporadic inclusion-body myositis, the most common muscle disease of older persons, has no known cause or persistently beneficial treatment. The unfolding pathogenesis could lead to new treatment strategies and it is now of growing interest among clinicians and basic scientists. About 100 papers related to the subject were published in 2006 and the first part of 2007 (we cite only articles most relevant to this review). This review focuses on the current concepts of the pathogenesis of sporadic inclusion-body myositis. Both degeneration and mononuclear-cell inflammation are components of the pathology, but how each relates to the pathogenesis remains unclear. We suggest that an intramuscle fiber degenerative component is primary, leading to muscle-fiber destruction, while the lymphocytic inflammatory component may only slightly contribute to sporadic inclusion-body myositis muscle-fiber damage. Intracellular accumulation of amyloid-beta precursor protein, amyloid-beta, and amyloid-beta oligomers in an aging muscle-fiber cellular milieu, and other abnormalities, appear to be key pathogenic factors. We summarize intracellular molecular events and their consequences, and correlate findings in sporadic inclusion-body myositis muscle biopsies with inclusion-body myositis experimental models in tissue culture and in transgenic mice. Treatment of sporadic inclusion-body myositis remains a challenge. Antiinflammatory approaches used so far are without major or enduring benefit. Possible new treatment avenues are suggested.

NOGO is increased and binds to BACE1 in sporadic inclusion-body myositis and in AβPP-overexpressing cultured human muscle fibers

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.

Inclusion body myositis and myopathies.

Preface Part I. Overview of Pathologic and Pathogenic Comparison Between Sporadic Inclusion-Body Myositis and Hereditary Inclusion-Body Myopathies: 1. Newest approaches to diagnosis and pathogenesis of sporadic inclusion-body myositis and hereditary inclusion-body myopathies, including molecular-pathologic similarities to Alzheimer disease Part II. Historical Perspective: 2: Evolving concepts of inclusion-body myositis Part III. Sporadic Inclusion-Body Myositis - Clinical and Diagnostic Considerations: 3: Sporadic inclusion-body myositis: Clinical and laboratory features and diagnostic criteria 4: Inclusion-body myositis: natural history 5: Uncommon clinico-pathological forms of sporadic inclusion-body myositis: Report of four cases 6: Inclusion-body myositis: pathological changes 7: Unusual pathological forms of inclusion-body myositis, and neuromuscular disorders with IBM-like changes 8: Electrophysiological findings in inclusion-body myositis 9: Genetic factors in sporadic inclusion-body myositis Part IV. Hereditary Inclusion-Body Myopathies - Clinical and Diagnostic Considerations: 10: Hereditary inclusion-body myopathy in Jews of Persian origin: Clinical and laboratory data 11. Hereditary inclusion-body myopathy (h-IBM) with quadriceps sparing: epidemiology and genetics 12: Familial autosomal-recessive inclusion-body myositis with asymptomatic leukoencephalopathy 13: Welander distal myopathy - clinical, pathophysiological, and molecular aspects 14. Tibial muscular dystrophy - clinical, genetic, and morphological characteristics 15. Distal myopathy with rimmed vacuoles, inclusion-body myositis and related disorders in Japan 16. Inclusion-body myopathies 17. Is the muscle fiber in inclusion body-myositis an antigen-presenting cell of an innocent bystander? 18. Viruses, immunodeficiency and inclusion-body myositis 19. Myonuclear abnormalities may play a central role in the pathogenesis of muscle fiber damage in inclusion-body myositis 20. Nuclear degeneration and rimmed vacuole formation in neuromuscular disorders 21. Mitochondrial alterations in sporadic inclusion-body myositis 22. mtDNA analysis in muscle of patients with sporadic inclusion-body myopathy Part V. Treatment: 23. Evaluation of treatment for sporadic inclusion-body myositis 24. Personal experience in treating sporadic inclusion-body myositis Subject index.