Alterations of redox dynamics and desmin post-translational modifications in skeletal muscle models of desminopathies

Delort, Florence; Ségard, Bertrand-David; Hakibilen, Coralie; Bourgois-Rocha, Fany; Cabet, Eva; Vicart, Patrick; Huang, Meng‐Er; Clary, Guilhem; Lilienbaum, Alain; Agbulut, Onnik; Batonnet-Pichon, Sabrina

doi:10.1016/j.yexcr.2019.111539

Cited by 9 publications

(12 citation statements)

References 56 publications

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“…Interestingly, two bands corresponding to endogenous (mouse, lower band) and exogenous (human, higher band) desmin were revealed with anti-desmin specific antibodies, allowing us to quantify the ratio between the two forms. As previously reported ( Delort et al, 2019 ), endogenous desmin was always more highly expressed than exogenous desmin ( Figure 1A , the ratio of exogenous/endogenous varies from 0.1 to 0.7), corresponding to moderate desmin overexpression close to the pathophysiological conditions observed in patients.…”

Section: Resultssupporting

confidence: 86%

Desmin Modulates Muscle Cell Adhesion and Migration

Hakibilen

Delort

Daher

et al. 2022

Front. Cell Dev. Biol.

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Cellular adhesion and migration are key functions that are disrupted in numerous diseases. We report that desmin, a type-III muscle-specific intermediate filament, is a novel cell adhesion regulator. Expression of p.R406W mutant desmin, identified in patients with desmin-related myopathy, modified focal adhesion area and expression of adhesion-signaling genes in myogenic C2C12 cells. Satellite cells extracted from desmin-knock-out (DesKO) and desmin-knock-in-p.R405W (DesKI-R405W) mice were less adhesive and migrated faster than those from wild-type mice. Moreover, we observed mislocalized and aggregated vinculin, a key component of cell adhesion, in DesKO and DesKI-R405W muscles. Vinculin expression was also increased in desmin-related myopathy patient muscles. Together, our results establish a novel role for desmin in cell-matrix adhesion, an essential process for strength transmission, satellite cell migration and muscle regeneration. Our study links the patho-physiological mechanisms of desminopathies to adhesion/migration defects, and may lead to new cellular targets for novel therapeutic approaches.

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Section: Resultssupporting

confidence: 86%

Desmin Modulates Muscle Cell Adhesion and Migration

Hakibilen

Delort

Daher

et al. 2022

Front. Cell Dev. Biol.

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“…Although apoptosis is a beneficial survival response in mitotic tissues, it has limited benefits in post-mitotic cells such as muscle that are limited to satellite cell mediated repair [ 56 ]. Through its effects on protein structure, function, aggregation, and apoptosis, oxidative stress could further exacerbate sarcomere disarray and myofiber degeneration in MFM WB [ 51 , 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Integrated proteomic and transcriptomic profiling identifies aberrant gene and protein expression in the sarcomere, mitochondrial complex I, and the extracellular matrix in Warmblood horses with myofibrillar myopathy

et al. 2021

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Background Myofibrillar myopathy in humans causes protein aggregation, degeneration, and weakness of skeletal muscle. In horses, myofibrillar myopathy is a late-onset disease of unknown origin characterized by poor performance, atrophy, myofibrillar disarray, and desmin aggregation in skeletal muscle. This study evaluated molecular and ultrastructural signatures of myofibrillar myopathy in Warmblood horses through gluteal muscle tandem-mass-tag quantitative proteomics (5 affected, 4 control), mRNA-sequencing (8 affected, 8 control), amalgamated gene ontology analyses, and immunofluorescent and electron microscopy. Results We identified 93/1533 proteins and 47/27,690 genes that were significantly differentially expressed. The top significantly differentially expressed protein CSRP3 and three other differentially expressed proteins, including, PDLIM3, SYNPO2, and SYNPOL2, are integrally involved in Z-disc signaling, gene transcription and subsequently sarcomere integrity. Through immunofluorescent staining, both desmin aggregates and CSRP3 were localized to type 2A fibers. The highest differentially expressed gene CHAC1, whose protein product degrades glutathione, is associated with oxidative stress and apoptosis. Amalgamated transcriptomic and proteomic gene ontology analyses identified 3 enriched cellular locations; the sarcomere (Z-disc & I-band), mitochondrial complex I and the extracellular matrix which corresponded to ultrastructural Z-disc disruption and mitochondrial cristae alterations found with electron microscopy. Conclusions A combined proteomic and transcriptomic analysis highlighted three enriched cellular locations that correspond with MFM ultrastructural pathology in Warmblood horses. Aberrant Z-disc mechano-signaling, impaired Z-disc stability, decreased mitochondrial complex I expression, and a pro-oxidative cellular environment are hypothesized to contribute to the development of myofibrillar myopathy in Warmblood horses. These molecular signatures may provide further insight into diagnostic biomarkers, treatments, and the underlying pathophysiology of MFM.

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“…As for LMNA-RD, close cardiac monitoring in desminopathy patients is highly recommended from adolescence [59]. Heart disease in desminopathy may precede, follow or be concomitant with skeletal myopathy, as also observed in LMNA-RD, and there is no correlation with the severity of skeletal muscle weakness [51,54,59,60]. In addition, as for laminopathies, cardiac disease in desminopathy may manifest with arrhythmias and/or cardiomyopathy, although arrhythmias are quite rare in desminopathy and frequent in muscular laminopathies [54,59].…”

Section: Clinical Aspects Of Cardiac Involvement In Desminopathiesmentioning

confidence: 99%

“…Moreover, MnSOD and/or catalase overexpression in desmin null mouse heart was sufficient to reduce intracellular ROS and improve cardiac function [81]. Formation of desmin aggregates has been also tested in the presence of anti-oxidants, as N-acetyl-cysteine (NAC), in cultured desminopathic cells [60]. Although NAC prevented aggregate formation in desmin mutant cultured cells, it failed to reduce aggregates in mutant muscle [60].…”

Section: Pathogenesis Of Desminopathiesmentioning

confidence: 99%

“…Formation of desmin aggregates has been also tested in the presence of anti-oxidants, as N-acetyl-cysteine (NAC), in cultured desminopathic cells [60]. Although NAC prevented aggregate formation in desmin mutant cultured cells, it failed to reduce aggregates in mutant muscle [60]. We could hypothesize that rescue of a functional connection between desmin and mitochondria is necessary to avoid accumulation of mitochondrial defects and the oxidative stress condition induced by mutated desmin.…”

Section: Pathogenesis Of Desminopathiesmentioning

confidence: 99%

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Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

Maggi

Mavroidis

Psarras

et al. 2021

IJMS

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Intermediate filaments are major components of the cytoskeleton. Desmin and synemin, cytoplasmic intermediate filament proteins and A-type lamins, nuclear intermediate filament proteins, play key roles in skeletal and cardiac muscle. Desmin, encoded by the DES gene (OMIM *125660) and A-type lamins by the LMNA gene (OMIM *150330), have been involved in striated muscle disorders. Diseases include desmin-related myopathy and cardiomyopathy (desminopathy), which can be manifested with dilated, restrictive, hypertrophic, arrhythmogenic, or even left ventricular non-compaction cardiomyopathy, Emery–Dreifuss Muscular Dystrophy (EDMD2 and EDMD3, due to LMNA mutations), LMNA-related congenital Muscular Dystrophy (L-CMD) and LMNA-linked dilated cardiomyopathy with conduction system defects (CMD1A). Recently, mutations in synemin (SYNM gene, OMIM *606087) have been linked to cardiomyopathy. This review will summarize clinical and molecular aspects of desmin-, lamin- and synemin-related striated muscle disorders with focus on LMNA and DES-associated clinical entities and will suggest pathogenetic hypotheses based on the interplay of desmin and lamin A/C. In healthy muscle, such interplay is responsible for the involvement of this network in mechanosignaling, nuclear positioning and mitochondrial homeostasis, while in disease it is disturbed, leading to myocyte death and activation of inflammation and the associated secretome alterations.

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Alterations of redox dynamics and desmin post-translational modifications in skeletal muscle models of desminopathies

Cited by 9 publications

References 56 publications

Desmin Modulates Muscle Cell Adhesion and Migration

Desmin Modulates Muscle Cell Adhesion and Migration

Integrated proteomic and transcriptomic profiling identifies aberrant gene and protein expression in the sarcomere, mitochondrial complex I, and the extracellular matrix in Warmblood horses with myofibrillar myopathy

Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

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