Desminopathies in muscle disease

Paulin, Denise; Huet, Alexis; Khanamyrian, Luiza; Xue, Zhigang

doi:10.1002/path.1639

Cited by 78 publications

(69 citation statements)

References 51 publications

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“…Desmin mutations can result in various myopathies that are characterized by desmin network disorganization, accumulation of insoluble desmin‐containing aggregates, and sarcomere disarray 9, 36, 37. Expression of the 7 amino acid deletion (R173–E179) mutation in desmin leads to a desminopathy characterized by defects in skeletal, cardiac, and smooth muscle 38, 39.…”

Section: Discussionmentioning

confidence: 99%

“…Muscle biopsy specimens from human desminopathies and myofibrillar myopathies showed evidence of mitochondrial pathology 43, 44. Moreover, patients with mutations in desmin, αB‐crystallin, filamin‐C, myotilin, ZASP, FHL1, and plectin, which are all causative of myofibrillar myopathies, showed mitochondrial dysfunction 36. The functional relationship between altered mitochondrial dynamics and function caused by these disease‐causing mutations remains mostly unknown in the majority of these diseases.…”

Section: Discussionmentioning

confidence: 99%

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Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

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BackgroundDesmin filament proteins interlink the contractile myofibrillar apparatus with mitochondria, nuclei and the sarcolemma. Mutations in the human desmin gene cause cardiac disease, remodeling, and heart failure but the pathophysiological mechanisms remain unknown.Methods and ResultsCardiomyocyte‐specific overexpression of mutated desmin (a 7 amino acid deletion R172‐E178, D7‐Des Tg) causes accumulations of electron‐dense aggregates and myofibrillar degeneration associated with cardiac dysfunction. Though extensive studies demonstrated that these altered ultrastructural changes cause impairment of cardiac contractility, the molecular mechanism of cardiomyocyte death remains elusive. In the present study, we report that the D7‐Des Tg mouse hearts undergo aberrant mitochondrial fission associated with increased expression of mitochondrial fission regulatory proteins. Mitochondria isolated from D7‐Des Tg hearts showed decreased mitochondrial respiration and increased apoptotic cell death. Overexpression of mutant desmin by adenoviral infection in cultured cardiomyocytes led to increased mitochondrial fission, inhibition of mitochondrial respiration, and activation of cellular toxicity. Inhibition of mitochondrial fission by mitochondrial division inhibitor mdivi‐1 significantly improved mitochondrial respiration and inhibited cellular toxicity associated with D7‐Des overexpression in cardiomyocytes.ConclusionsAberrant mitochondrial fission results in mitochondrial respiratory defects and apoptotic cell death in D7‐Des Tg hearts. Inhibition of aberrant mitochondrial fission using mitochondrial division inhibitor significantly preserved mitochondrial function and decreased apoptotic cell death. Taken together, our study shows that maladaptive aberrant mitochondrial fission causes desminopathy‐associated cellular dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

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“…From these investigations, it has been concluded that all mutant desmin proteins are unable to assemble into bona fide IFs (7,19). In contrast, it has recently been demonstrated that even a mutation in an IF-consensus motif in the epidermal keratin, K14, does not necessarily inhibit the formation of bona fide IFs in the test tube (20,21); although, in affected patient epidermal cells, the protein assembles into huge aggregates causing severe epidermolysis (22,23).…”

Section: Discussionmentioning

confidence: 99%

Severe muscle disease-causing desmin mutations interfere with in vitro filament assembly at distinct stages

Bär

Mücke

Kostareva

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

118

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Desmin is the major intermediate filament (IF) protein of muscle.Recently, mutations of the desmin gene have been reported to cause familial or sporadic forms of human skeletal, as well as cardiac, myopathy, termed desmin-related myopathy (DRM). The impact of any of these mutations on filament assembly and integration into the cytoskeletal network of myocytes is currently not understood, despite the fact that all cause the same histopathological defect, i.e., desmin aggregation. To gain more insight into the molecular basis of this process, we investigated how mutations within the ␣-helical rod domain of desmin affect both the assembly of the recombinant protein in vitro as well as the filament-forming capacity in cDNA-transfected cells. Whereas 6 of 14 mutants assemble into seemingly normal IFs in the test tube, the other mutants interfere with the assembly process at distinct stages, i.e., tetramer formation, unit-length filament (ULF) formation, filament elongation, and IF maturation. Correspondingly, the mutants with in vitro assembly defects yield dot-like aggregates in transfected cells, whereas the mutants that form IFs constitute a seemingly normal IF cytoskeleton in the cellular context. At present, it is entirely unclear why the latter mutant proteins also lead to aggregate formation in myocytes. Hence, these findings may be a starting point to dissect the contribution of the individual subdomains for desmin pathology and, eventually, the development of therapeutic interventions.desmin-related myopathy ͉ intermediate filaments

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“…These experiments show that desmin is essential for the structural integrity of skeletal muscle, but not for myogenic commitment, differentiation, or fusion of myoblasts. 87 Analysis of transgenic mice has provided insights into the mechanisms of intracellular protein aggregation. In transgenic mice expressing a human mutation p.Arg173_Glu179del, examination of the myocardium reveals an accumulation of chimeric intracellular aggregates containing desmin and other cytoskeletal proteins.…”

Section: Animal Modelsmentioning

confidence: 99%

Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

104

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Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin. The inheritance pattern in familial desminopathy is characterized as autosomal dominant or autosomal recessive, but many cases have no family history. At least some and likely most sporadic desminopathy cases are associated with de novo DES mutations. The age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Typically, the illness presents with lower and later upper limb muscle weakness slowly spreading to involve truncal, neckflexor, facial and bulbar muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks, arrhythmias and chronic heart failure resulting in premature sudden death. Respiratory muscle weakness is a major complication in some patients. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing chimeric aggregates consisting of desmin and other cytoskeletal proteins. Various DES gene mutations: point mutations, an insertion, small in-frame deletions and a larger exon-skipping deletion, have been identified in desminopathy patients. The majority of these mutations are located in conserved alpha-helical segments, but additional mutations have recently been identified in the tail domain. Filament and network assembly studies indicate that most but not all disease-causing mutations make desmin assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. AlphaBcrystallin serves as a chaperone for desmin preventing its aggregation under various forms of stress; mutant CRYAB causes cardiac and skeletal myopathies identical to those resulting from DES mutations.

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Desminopathies in muscle disease

Abstract: A recently identified class of myopathies is produced by abnormal desmin, and is characterized by a disorganization of the desmin filament network, the accumulation of insoluble desmin-containing aggregates, and destructive changes in the sarcomeric organization of striated muscles.

Cited by 78 publications

References 51 publications

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

Severe muscle disease-causing desmin mutations interfere with in vitro filament assembly at distinct stages

Intermediate Filament Diseases: Desminopathy

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