Cardiovascular Lesions and Skeletal Myopathy in Mice Lacking Desmin

Li, Zhenlin; Colucci‐Guyon, Emma; Pinçon‐Raymond, Martine; Mericskay, Mathias; Pournin, Sandrine; Paulin, Denise; Babinet, Charles

doi:10.1006/dbio.1996.0122

Cited by 320 publications

(264 citation statements)

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“…Ablation of desmin expression in mice by gene targeting 21 has demonstrated that desmin expression is crucial for maintaining the architectural and functional integrity of striated muscle. Mice lacking desmin develop numerous muscle architectural and ultrastructural defects, especially in extensively used muscles such as the heart, soleus and diaphragm.…”

Section: Intermediate Filaments Of the Musclementioning

confidence: 99%

“…21,23,81 Some cell architecture defects such as misaligned muscle fibers, abnormal sarcomeres, swollen mitochondria and unusual distribution of myosins are seen in earlier stages of development. 86 After birth, irregularities in the myofibrillar organization are predominantly observed in the extensively used skeletal muscles such as the tongue, diaphragm and the soleus muscle.…”

Section: Animal Modelsmentioning

confidence: 99%

“…86 After birth, irregularities in the myofibrillar organization are predominantly observed in the extensively used skeletal muscles such as the tongue, diaphragm and the soleus muscle. 21,23,81 Mitochondria exhibit an increase in size and number, a loss of correct positioning and finally degeneration, which was especially pronounced after exercise overload. 23 Cardiac muscle is most susceptible to the lack of desmin.…”

Section: Animal Modelsmentioning

confidence: 99%

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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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Section: Intermediate Filaments Of the Musclementioning

confidence: 99%

Section: Animal Modelsmentioning

confidence: 99%

Section: Animal Modelsmentioning

confidence: 99%

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Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

104

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“…Those mice developed a progressive and generalized myopathy that mainly affected the myocardium. The striated muscles that were examined all showed irregular mitochondrial shape and distribution, including aggregation of sarcolemmal mitochondria, which correlated with weakened muscles and increased fatigue 4, 5…”

Section: Introductionmentioning

confidence: 99%

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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“…The ability of desmin and syncoilin to inter-act provides evidence for an important association between IF proteins at the Z-lines in muscle and the extracellular matrix via the DAPC. Mutations in the desmin gene cause myopathy together with cardiomyopathy (13). Syncoilin, like desmin, is up-regulated in some muscular dystrophies, making it a candidate gene for muscular dystrophy as well as cardiomyopathy.…”

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confidence: 99%

Association of Syncoilin and Desmin

Poon

Howman

Newey

et al. 2002

Journal of Biological Chemistry

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We recently identified a novel protein called syncoilin, a putative intermediate filament protein that interacts with ␣-dystrobrevin, a member of the dystrophin-associated protein complex. Syncoilin is found at the neuromuscular junction, sarcolemma, and Z-lines and is thought to be important for muscle fiber integrity. Based on the similar protein structure and cellular localization of syncoilin and desmin, we proposed that these proteins interact in vivo. The data presented confirm an interaction between syncoilin and desmin and demonstrate their co-localization in skeletal muscle. Intriguingly, whereas these proteins interact, COS-7 cell expression studies show that desmin and syncoilin do not assemble into heterofilaments. Furthermore, fractionation assay and immunofluorescence study of H2K myoblasts and myotubes suggest that, unlike typical intermediate filament proteins, syncoilin does not participate in filament formation with any protein. However, it is possible that syncoilin is involved in the anchoring of the desmin intermediate filament network at the sarcolemma and the neuromuscular junction. This interaction is likely to be important for maintaining muscle fiber integrity and may also link the dystrophin-associated protein complex to the cytoskeleton. The dysfunction or absence of syncoilin may result in the disruption of the intermediate filament network leading to muscle necrosis. Syncoilin is therefore an ideal candidate gene for muscular dystrophies and desmin-related myopathies.

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Cardiovascular Lesions and Skeletal Myopathy in Mice Lacking Desmin

Cited by 320 publications

References 0 publications

Intermediate Filament Diseases: Desminopathy

Intermediate Filament Diseases: Desminopathy

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

Association of Syncoilin and Desmin

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