Desmin myopathy: a multisystem disorder involving skeletal, cardiac, and smooth muscle

Ariza, Aurelio; Coll, J; Fernández‐Figueras, María Teresa; López, Montserrat; Mate, J L; García, Olga; Fernández-Vasalo, Angela; Navas‐Palacios, José J.

doi:10.1016/0046-8177(95)90095-0

Cited by 96 publications

(59 citation statements)

References 20 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. These patients are at risk for cerebrovascular accidents and may develop generalized muscle weakness, respiratory failure, and intestinal pseudo‐obstruction that can lead to death 38, 39.…”

Section: Discussionmentioning

confidence: 99%

“…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. These patients are at risk for cerebrovascular accidents and may develop generalized muscle weakness, respiratory failure, and intestinal pseudo‐obstruction that can lead to death 38, 39. Ultrastructural analysis of postmortem muscles show characteristic myofibrillar disruption and aggregation of desmin filaments in the myocardium 38, 39.…”

Section: Discussionmentioning

confidence: 99%

“…These patients are at risk for cerebrovascular accidents and may develop generalized muscle weakness, respiratory failure, and intestinal pseudo‐obstruction that can lead to death 38, 39. Ultrastructural analysis of postmortem muscles show characteristic myofibrillar disruption and aggregation of desmin filaments in the myocardium 38, 39. In addition, mitochondrial dysfunction occurs early and acts causally in a wide variety of human protein aggregate disease pathogenesis affecting the central nervous system40, 41 and striated muscle tissue 16, 42.…”

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%

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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“…A patient homozygous for deletion of seven amino acids in the 1B helix (p.Arg173_Glu179del), 10 developed generalized muscular weakness and atrophy, predominantly in distal muscles of the upper extremities, atrioventricular (AV) block requiring implantation of a permanent pacemaker and intestinal malabsorption. 102 EchoCG showed dilatation of the right cardiac chambers. Disease progression led to cardiac and respiratory failure and intestinal pseudo-obstruction.…”

Section: Disease Severity In Patients With Autosomal Recessive Inherimentioning

confidence: 99%

“…Immunohistochemical studies have consistently demonstrated the presence of inclusions or deposits reacting with antibodies against desmin and other proteins such as alphaB-crystallin and, although rarely investigated, synemin, 42,85,97 syncoilin, 109 plectin, 42,43 nestin, 6,85 dystrophin, 2,43,50 merosin, alpha-and beta-dystroglycan, alpha-, beta-, gamma-and deltasarcoglycans, utrophin, collagen VI, NOS, caveolin, dysferlin, beta-and gamma-laminin, actin, actinin, N-CAM, heat shock protein 72/73, 43 myotilin, 2,43,50 gamma-filamin, 50 vimentin, beta-spectrin 11 and ubiquitin.. 43,50,102 The size, shape and localization of protein aggregates differ from one case to another. These may be restricted to the subsarcolemmal regions or within the cytoplasm; they may be diffuse or well demarcated, and in some cases both diffuse and well demarcated small deposits are found in the same specimen (Fig.…”

Section: Skeletal Muscle Pathologymentioning

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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Smooth muscle inclusion bodies in slow transit constipation

et al. 2001

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Slow transit constipation (STC) is a disorder of intestinal motility of unknown aetiology. Myopathies, including those characterized by the finding of inclusion bodies, have been described in enteric disorders. Amphophilic inclusion bodies have been reported in the muscularis externa of the colon of STC patients. This study formally tested the hypothesis that these represent a primary muscle disorder, specific to STC. In a systematic, blinded, dual observer qualitative and quantitative analysis, colonic and ileal tissue from patients with STC (n=36) were compared with selected control populations: total colonic aganglionosis (n=10), Chagas' disease (n=6), isolated rectal evacuation disorders (n=6), and a control population of a range of ages (n=80). All sections were stained with haematoxylin and eosin and periodic acid Schiff. Further immunostains were used in an attempt to determine inclusion body composition. Round or ovoid (4-22 microm diameter) amphophilic inclusions increased in number in normal subjects with age. Inclusions were more frequent in idiopathic STC than in age-matched controls or rectal evacuation disorders [ileum (33% vs. 9%), ascending (50% vs. 19%, p<0.05), and sigmoid colon (43% vs. 20%)] and were very frequent in the sigmoid (71%) of patients with STC arising after pelvic surgery. The number of inclusions per unit area was significantly higher in patients with STC (p<0.001). Inclusions were found in all Chagas' patients, but not with aganglionosis. It was not possible to determine inclusion body composition, despite the use of a wide range of conventional and immunostains. This study demonstrates that inclusion body myopathy is identifiable in patients with STC and that it may arise secondary to denervation.

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Desmin myopathy: a multisystem disorder involving skeletal, cardiac, and smooth muscle

Cited by 96 publications

References 20 publications

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

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

Intermediate Filament Diseases: Desminopathy

Smooth muscle inclusion bodies in slow transit constipation

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