Sporadic inclusion body myositis: clinical, pathological, and genetic analysis of eight Polish patients

Kierdaszuk, Biruta; Berdyński, Mariusz; Palczewski, Piotr; Gołębiowski, Marek; Żekanowski, Cezary; Kamińska, Anna

doi:10.5114/fn.2015.56550

Cited by 13 publications

(20 citation statements)

References 17 publications

(28 reference statements)

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“…In most cases we saw myofiber atrophy with subsequent invasion of connective and adipose tissue. The results are in accordance with observations made by others [12,17,27,36,37]. In a few cases hypertrophic myofibers in IBM patients were also reported [12,27].…”

Section: Discussionsupporting

confidence: 93%

“…However, muscle fiber hypertrophy seems to be more characteristic of skeletal muscle dystrophies than inflammatory myopathy [38]. We have also demonstrated the presence of necrotic myofibers which could occur in muscles of IBM patients, as was described by Kierdaszuk et al [37]. The necrotic process is probably caused by the action of perforin and granzymes, enzymes secreted by T lymphocytes [15].…”

Section: Discussionsupporting

confidence: 77%

“…We found that skeletal muscle biopsies of IBM patients presented typical changes which have been well described by others, including hypertrophy of connective and adipose tissues, focal occurrence of necrotic fibers, RVs, a pattern of inflammatory cell infiltrations or pathological protein aggregates [3,4,9,12,17,37]. In most cases we saw myofiber atrophy with subsequent invasion of connective and adipose tissue.…”

Section: Discussionsupporting

confidence: 72%

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Immunohistochemical and ultrastructural analysis of sporadic inclusion body myositis: a case series

et al. 2018

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Sporadic inclusion body myositis (s-IBM) is a progressive, skeletal muscle disease with poor prognosis. However, establishing the final diagnosis is difficult because of the lack of clear biomarkers in the blood serum and very slow development of clinical symptoms. Moreover, most other organs function normally without any disturbance. Here, in patients with this untreatable disease, we have underlined the importance of immunohistochemical and ultrastructural assessment of skeletal muscle in patients diagnosed with s-IBM. The goal of this study was to identify the distribution of specific antigens and to determine morphological features in order to localize pathological protein aggregates, rimmed vacuoles, and loss of myofibrils, which are key elements in the diagnosis of s-IBM. All studied patients were between 48 and 83 years of age and were hospitalized in the Department of Rheumatology and Internal Medicine between 2011 and 2016. Anamneses revealed an accelerated progression of muscle atrophy, weakness of limb muscles, and difficulties with climbing stairs. Based on histopathology and transmission electron microscopy examination, inflammatory infiltrations consisting of mononuclear cells, severe atrophy and focal necrosis of myofibers, splitting of myofilaments, myelinoid bodies and rimmed vacuoles were observed. Primary antibodies directed against CD3, CD8, CD68, cN1A, beta-amyloid, Tau protein and apolipoprotein B made it possible to identify types of cells within infiltrations as well as the protein deposits within myofibers. Using a combination of immunohistochemistry and electron microscopy methods, we were able to establish the correct final diagnosis and to implement a specific treatment to inhibit disease progression.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 72%

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Immunohistochemical and ultrastructural analysis of sporadic inclusion body myositis: a case series

et al. 2018

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“…1A). By electron microscopy myofibrillar disorganization [15] was observed in 3 patients (patients 1, 3, and 4; Table 1). Two patients (patients 1 and 3; Table 1) had mitochondrial abnormalities with concentric cristae and enlarged mitochondria ( Fig.…”

Section: Defects In Mitochondrial Function In Sibmmentioning

confidence: 98%

“…Endomysial mononuclear cell infiltration was observed in 8 out of 9 patients, and there were many atrophic or hypertrophic muscle fibers with internal nuclei and splitting; both endomysial inflammation and muscle fiber degeneration were found to be characteristic of sIBM [4] (Table 1). All the samples showed rimmed vacuoles by modified Gomori trichrome (mGT) staining [15] (Table 1, Fig. 1A).…”

Section: Defects In Mitochondrial Function In Sibmmentioning

confidence: 99%

Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5

Oikawa

Izumi

Koide

et al. 2020

Preprint

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KeywordsSporadic inclusion body myositis (sIBM), mitochondrial dysfunction, GDF15, fusion/fission, mitochondrial dynamics, mitochonic acid-5 (MA-5) Short titles: MA-5 improved sIBM mitochondria Abbreviations:MA-5, 4-(2,4-difluorophenyl)-2-(1H-indole-3-yl)-4-oxobutanoic acid; MELAS, myopathy encephalopathy; sIBM, sporadic inclusion body myositis; GDF15, growth differential factor 15; COX, cytochrome oxidase; mtDNA, mitochondrial DNA; mtROS, mitochondrial reactive oxygen species; CK, creatine kinase; mGT, Gomori trichrome; OCR, oxygen consumption rate; ECAR, extracellular acidification rate; OXPHOS, oxidative phosphorylation; BSO, L-buthionine-(S, R)-sulfoximine; ND1, NADH dehydrogenase 1; Opa1, optic atrophy 1; Drp1, dynamin-related protein 1 This PDF file includes: Supplementary textFigures S1 to S10 Tables S1 to S3 Legends for Movies S1 to S2 Other supplementary materials for this manuscript include the following:Movies S1 to S2 Abstract Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology.We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function.Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction.Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death.MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the production, protecting patients with mitochondrial dysfunction from fibroblast death [10][11][12]. It also prolongs the survival of a mouse model of mitochondrial disease [11]. This sparked our interest in using MA-5 to treat sIBM. Here, we demonstrated a significant elevation of a mitochondrial disease biomarker, growth differential factor 15 (GDF15) [13], in sIBM patient serum and found mitochondrial dysfunction in both patient myoblasts and skin fibroblasts. Under these conditions, MA-5 improved cell survival, increased ATP, and improved mitochondrial morphology and dynamics, suggesting the potential of MA-5 for sIBM therapy. 7 Materials and Methods Compounds MA-5,4-(2,4-difluorophenyl)-2-(1H-indole-3-yl)-4-oxobutanoic acid was chemically synthesized at Okayama University of Science as previously reported[10]. BSO (Lbuthionine-[S,R]-sulfoximine) was purchased from Wako Pure Chemical Industries. Primary myoblast isolationThe tissue samples were washed with normal saline to remove b...

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Endoplasmic Reticulum Stress Induces Myostatin High Molecular Weight Aggregates and Impairs Mature Myostatin Secretion

et al. 2018

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Sporadic inclusion body myositis (sIBM) is the most prevalent acquired muscle disorder in the elderly with no defined etiology or effective therapy. Endoplasmic reticulum stress and deposition of myostatin, a secreted negative regulator of muscle growth, have been implicated in disease pathology. The myostatin signaling pathway has emerged as a major target for symptomatic treatment of muscle atrophy. Here, we systematically analyzed the maturation and secretion of myostatin precursor MstnPP and its metabolites in a human muscle cell line. We find that increased MsntPP protein levels induce ER stress. MstnPP metabolites were predominantly retained within the endoplasmic reticulum (ER), also evident in sIBM histology. MstnPP cleavage products formed insoluble high molecular weight aggregates, a process that was aggravated by experimental ER stress. Importantly, ER stress also impaired secretion of mature myostatin. Reduced secretion and aggregation of MstnPP metabolites were not simply caused by overexpression, as both events were also observed in wildtype cells under ER stress. It is tempting to speculate that reduced circulating myostatin growth factor could be one explanation for the poor clinical efficacy of drugs targeting the myostatin pathway in sIBM.Electronic supplementary materialThe online version of this article (10.1007/s12035-018-0997-9) contains supplementary material, which is available to authorized users.

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Sporadic inclusion body myositis: clinical, pathological, and genetic analysis of eight Polish patients

Abstract: A b s t r a c t Introduction: Sporadic inclusion body myositis (sIBM) is one of the most common myopathies in patients above

Cited by 13 publications

References 17 publications

Immunohistochemical and ultrastructural analysis of sporadic inclusion body myositis: a case series

Immunohistochemical and ultrastructural analysis of sporadic inclusion body myositis: a case series

Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5

Endoplasmic Reticulum Stress Induces Myostatin High Molecular Weight Aggregates and Impairs Mature Myostatin Secretion

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