Autophagic vacuolar pathology in desminopathies

Weihl, Conrad C.; Iyadurai, Stanley; Baloh, Robert H.; Pittman, Sara K.; Schmidt, Robert E.; Lopate, Glenn; Pestronk, Alan; Harms, Matthew B.

doi:10.1016/j.nmd.2014.12.002

Cited by 21 publications

(17 citation statements)

References 28 publications

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“…The intriguing fact is that, we saw a subset of biopsies harboring vacuoles prompted us to quantify them and to study their characteristics in detail. Not only were they scarce in most cases, but they also differed from vacuoles described in sIBM (8,10,14,19,21,33) and from the ones described in childhood or adult autophagic vacuolar myopathies (15,27,31,32,43). Vacuoles in IMNM never showed signs of the sarcolemmal lining by immunohistochemistry or electron microscopy.…”

Section: Discussionmentioning

confidence: 76%

Sequestosome‐1 (p62) expression reveals chaperone‐assisted selective autophagy in immune‐mediated necrotizing myopathies

et al. 2019

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Diffuse myofiber necrosis in the context of inflammatory myopathy is the hallmark of immune‐mediated necrotizing myopathy (IMNM). We have previously shown that skeletal muscle fibers of IMNM patients may display nonrimmed vacuoles and sarcoplasmic irregularities. The dysfunctional chaperone activity has been linked to the defective assembly of skeletal muscle proteins and their degradation via lysosomes, autophagy and the proteasomal machinery. This study was undertaken to highlight a chaperone‐assisted selective autophagy (CASA) pathway, functionally involved in protein homeostasis, cell stress and the immune response in skeletal muscle of IMNM patients. Skeletal muscle biopsies from 54 IMNM patients were analyzed by immunostaining, as well as by qPCR. Eight biopsies of sIBM patients served as pathological controls, and eight biopsies of nondisease control subjects were included. Alteration of autophagy was detectable in all IMNM biopsy samples highlighted via a diffuse sarcoplasmic staining pattern by p62 and LC3 independent of vacuoles. This pattern was at variance with the coarse focal staining pattern mostly confined to rimmed vacuoles in sIBM. Colocalization of p62 with the chaperone proteins HSP70 and αB‐crystalline points to the specific targeting of misfolded proteins to the CASA machinery. Bcl2‐associated athanogene 3 (BAG3) positivity of these fibers emphasizes the selectivity of autophagy processes and these fibers also express MHC class I sarcolemma. Expression of genes involved in autophagy and endoplasmic reticulum (ER) stress pathways studied here is significantly upregulated in IMNM. We highlight that vacuoles without sarcolemmal features may arise in IMNM muscle biopsies, and they must not be confounded with sIBM‐specific vacuoles. Further, we show the activation of selective autophagy and emphasize the role of chaperones in this context. CASA occurs in IMNM muscle, and specific molecular pathways of autophagy differ from the ones in sIBM, with p62 as a unique identifier of this process.

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Section: Discussionmentioning

confidence: 76%

Sequestosome‐1 (p62) expression reveals chaperone‐assisted selective autophagy in immune‐mediated necrotizing myopathies

et al. 2019

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“…It is notable that mutations in the intermediate filament desmin causes a myopathy with rimmed vacuoles. 10 …”

Section: Discussionmentioning

confidence: 99%

Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis

Güttsches

Brady

Krause

et al. 2017

Annals of Neurology

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Objective Sporadic inclusion body myositis (sIBM) pathogenesis is unknown; however, rimmed vacuoles (RVs) are a constant feature. We propose to identify proteins that accumulate within RVs. Methods RVs and intact myofibers were laser microdissected from skeletal muscle of 18 sIBM patients and analyzed by a sensitive mass spectrometry approach using label-free spectral count-based relative protein quantification. Whole exome sequencing was performed on 62 sIBM patients. Immunofluorescence was performed on patient and mouse skeletal muscle. Results 213 proteins were enriched by >1.5X in RVs compared to controls and included proteins previously reported to accumulate in sIBM tissue or when mutated cause myopathies with RVs. Proteins associated with protein folding and autophagy were the largest group represented. One autophagic adaptor protein not previously identified in sIBM was FYCO1. Rare missense coding FYCO1 variants were present in 11.3% of sIBM patients compared with 2.6% of controls (p=0.003). FYCO1 co-localized at RVs with autophagic proteins such as MAP1LC3 and SQSTM1 in sIBM and other RV myopathies. One FYCO1 variant protein had reduced co-localization with MAP1LC3 when expressed in mouse muscle. Interpretation This study used an unbiased proteomic approach to identify RV proteins in sIBM that included a novel protein involved in sIBM pathogenesis. FYCO1 accumulates at RVs and rare missense variants in FYCO1 are overrepresented in sIBM patients. These FYCO1 variants may impair autophagic function leading to RV formation in sIBM patient muscle. FYCO1 functionally connects autophagic and endocytic pathways supporting the hypothesis that impaired endolysosmal degradation underlies the pathogenesis of sIBM.

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“…[11,[27][28][29][30]) and a limited number of reports of COX-negative fibres in muscle from affected patients [27,[29][30][31]. Enlarged, vacuolated mitochondria [28,30,32], mitochondria with abnormal cristae [29,33] and mitochondria containing paracrystalline inclusions [11,29] have been described in desminopathy patients. A subtle complex I deficiency was reported in the muscle of one patient [27].…”

Section: Desminopathymentioning

confidence: 99%

Mitochondrial abnormalities in the myofibrillar myopathies

Jackson

Schäefer

Meinhardt

et al. 2015

Euro J of Neurology

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Myofibrillar myopathies are a genetically diverse group of skeletal muscle disorders, with distinctive muscle histopathology. Causative mutations have been identified in the genes MYOT, LDB3, DES, CRYAB, FLNC, BAG3, DNAJB6, FHL1, PLEC and TTN, which encode proteins which either reside in the Z-disc or associate with the Z-disc. Mitochondrial abnormalities have been described in muscle from patients with a myofibrillar myopathy. We reviewed the literature to determine the extent of mitochondrial dysfunction in each of the myofibrillar myopathy subtypes. Abnormal mitochondrial distribution is a frequent finding in each of the subtypes, but a high frequency of COX-negative or ragged red fibres, a characteristic finding in some of the conventional mitochondrial myopathies, is a rare finding. Few in vitro studies of mitochondrial function have been performed in affected patients.

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Autophagic vacuolar pathology in desminopathies

Cited by 21 publications

References 28 publications

Sequestosome‐1 (p62) expression reveals chaperone‐assisted selective autophagy in immune‐mediated necrotizing myopathies

Sequestosome‐1 (p62) expression reveals chaperone‐assisted selective autophagy in immune‐mediated necrotizing myopathies

Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis

Mitochondrial abnormalities in the myofibrillar myopathies

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