Inclusion body myositis: new insights into pathogenesis

Garlepp, Michael J.; Mastaglia, Frank

doi:10.1097/bor.0b013e328313644c

Cited by 15 publications

(4 citation statements)

References 50 publications

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“…The frequency of the disease is from 0.001% for those aged less than fifty years to about 0.005% for those aged over fifty 2 . Because of such a low frequency and rare occurrence, several years usually pass before the disease is diagnosed, as was the case with our patient 3 .…”

Section: Discussionsupporting

confidence: 51%

“…Numerous studies have hypothesized that IBM may be an autoimmune inflammatory muscle disorder. The lack of the adequate response to the administration of conventional therapeutic modules which are used in the treatment of autoimmune diseases points to the role of other factors in the pathogenesis of this disorder 3,4 . It is thought that IBM is closely connected to both autoimmune and degenerative processes.…”

Section: Introductionmentioning

confidence: 99%

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Physical therapy improves motion in a patient with inclusion body myositis - a case report

et al. 2020

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Authorship contribution Jelena Stevanović, Maja Vulović, Anita Ivošević, Miljana Aksić developed the study, reviewed literature, analyzed data and wrote one part of the manuscript. Andjelka Stojković, Aleksandar Radunović, analyzed data and wrote one part of the manuscript. Aleksandar Cvetković, Mihailo Bezmarević., Bojan Milosević, Milan Jovanović reviewed the literature and wrote one part of the manuscript. Danijela Pavićević collected data, developed the study, analyzed data and wrote one part of the manuscript.

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Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Physical therapy improves motion in a patient with inclusion body myositis - a case report

et al. 2020

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“…Taking our present in vitro data and the aforementioned clinical in vivo data together, abnormal extracellular TDP-43 accumulations are indeed sporadic and such TDP-43 abnormalities might occasionally be induced even under cell culture conditions wherein there are no other cell types such as immune cells that may directly and/or indirectly be related to the pathogenesis of sIBM 35 , 36 . In an attempt to elucidate possible pathogenic consequences related to abnormal cytosolic TDP-43 accumulation in sIBM myotubes, we examined expression levels of sortilin mRNA splicing variants including exo17b which is reportedly affected by TDP-43 abnormalities 37 , 38 , but identified no alterations in expression profiles between sIBM and healthy control myotubes regardless of whether or not EPS treatment was applied ( data not shown ).…”

Section: Discussionmentioning

confidence: 54%

Feeder-supported in vitro exercise model using human satellite cells from patients with sporadic inclusion body myositis

Chen

Ogawa

et al. 2022

Sci Rep

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Contractile activity is a fundamental property of skeletal muscles. We describe the establishment of a “feeder-supported in vitro exercise model” using human-origin primary satellite cells, allowing highly-developed contractile myotubes to readily be generated by applying electrical pulse stimulation (EPS). The use of murine fibroblasts as the feeder cells allows biological responses to EPS in contractile human myotubes to be selectively evaluated with species-specific analyses such as RT-PCR. We successfully applied this feeder-supported co-culture system to myotubes derived from primary satellite cells obtained from sporadic inclusion body myositis (sIBM) patients who are incapable of strenuous exercise testing. Our results demonstrated that sIBM myotubes possess essentially normal muscle functions, including contractility development, de novo sarcomere formation, and contraction-dependent myokine upregulation, upon EPS treatment. However, we found that some of sIBM myotubes, but not healthy control myotubes, often exhibit abnormal cytoplasmic TDP-43 accumulation upon EPS-evoked contraction, suggesting potential pathogenic involvement of the contraction-inducible TDP-43 distribution peculiar to sIBM. Thus, our “feeder-supported in vitro exercise model” enables us to obtain contractile human-origin myotubes, potentially utilizable for evaluating exercise-dependent intrinsic and pathogenic properties of patient muscle cells. Our approach, using feeder layers, further expands the usefulness of the “in vitro exercise model”.

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“…An additional mechanism for how myostatin/MstnPP contributes to sIBM is focused on increased activity by the myostatin growth factor. As myostatin is a procachectic growth factor postnatally, increased production and processing of MstnPP may result in increased levels of circulating myostatin growth factor and signalling that leads to atrophy [45] , [46] , [49] , though there is little evidence supporting this hypothesis. A number of peptide hormones, such as those in secretory granules of the endocrine system, have been found to aggregate into amyloids in secretory pathways in a regulated, functional manner [50] , [51] , so there is a possibility that myostatin aggregates are protective in the sIBM diseased state.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein

Starck

Sutherland-Smith

2010

PLoS ONE

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Myostatin, a negative regulator of muscle growth, has been implicated in sporadic inclusion body myositis (sIBM). sIBM is the most common age-related muscle-wastage disease with a pathogenesis similar to that of amyloid disorders such as Alzheimer's and Parkinson's diseases. Myostatin precursor protein (MstnPP) has been shown to associate with large molecular weight filamentous inclusions containing the Alzheimer's amyloid beta peptide in sIBM tissue, and MstnPP is upregulated following ER stress. The mechanism for how MstnPP contributes to disease pathogenesis is unknown. Here, we show for the first time that MstnPP is capable of forming amyloid fibrils in vitro. When MstnPP-containing Escherichia coli inclusion bodies are refolded and purified, a proportion of MstnPP spontaneously misfolds into amyloid-like aggregates as characterised by electron microscopy and binding of the amyloid-specific dye thioflavin T. When subjected to a slightly acidic pH and elevated temperature, the aggregates form straight and unbranched amyloid fibrils 15 nm in diameter and also exhibit higher order amyloid structures. Circular dichroism spectroscopy reveals that the amyloid fibrils are dominated by β-sheet and that their formation occurs via a conformational change that occurs at a physiologically relevant temperature. Importantly, MstnPP aggregates and protofibrils have a negative effect on the viability of myoblasts. These novel results show that the myostatin precursor protein is capable of forming amyloid structures in vitro with implications for a role in sIBM pathogenesis.

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Inclusion body myositis: new insights into pathogenesis

Cited by 15 publications

References 50 publications

Physical therapy improves motion in a patient with inclusion body myositis - a case report

Physical therapy improves motion in a patient with inclusion body myositis - a case report

Feeder-supported in vitro exercise model using human satellite cells from patients with sporadic inclusion body myositis

Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein

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