Storage of phosphorylated desmin in a familial myopathy

Rappaport, L.; Contard, F.; Samuel, J. L.; Delcayre, Claude; Marotte, F.; Tomé, Fernando; Fardeau, Michel

doi:10.1016/0014-5793(88)80863-9

Cited by 103 publications

(40 citation statements)

References 15 publications

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“…Thus, there are 5-6 desmin isoforms in Purkinje fibers, specialized conducting cells in the heart of large mammalians (15). In people with familial congenital heart disease, there are also 5-6 isoforms (16). We could show that there are five desmin isoforms in the electric organs of the electric eel Electrophorus electricus L. (17).…”

Section: Biochemical Aspectsmentioning

confidence: 84%

Desmin: molecular interactions and putative functions of the muscle intermediate filament protein

Costa

Escaleira

Cataldo

et al. 2004

Braz J Med Biol Res

120

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Desmin is the intermediate filament (IF) protein occurring exclusively in muscle and endothelial cells. There are other IF proteins in muscle such as nestin, peripherin, and vimentin, besides the ubiquitous lamins, but they are not unique to muscle. Desmin was purified in 1977, the desmin gene was characterized in 1989, and knock-out animals were generated in 1996. Several isoforms have been described. Desmin IFs are present throughout smooth, cardiac and skeletal muscle cells, but can be more concentrated in some particular structures, such as dense bodies, around the nuclei, around the Z-line or in costameres. Desmin is up-regulated in muscle-derived cellular adaptations, including conductive fibers in the heart, electric organs, some myopathies, and experimental treatments with drugs that induce muscle degeneration, like phorbol esters. Many molecules have been reported to associate with desmin, such as other IF proteins (including members of the membrane dystroglycan complex), nebulin, the actin and tubulin binding protein plectin, the molecular motor dynein, the gene regulatory protein MyoD, DNA, the chaperone αB-crystallin, and proteases such as calpain and caspase. Desmin has an important medical role, since it is used as a marker of tumors' origin. More recently, several myopathies have been described, with accumulation of desmin deposits. Yet, after almost 30 years since its identification, the function of desmin is still unclear. Suggested functions include myofibrillogenesis, mechanical support for the muscle, mitochondrial localization, gene expression regulation, and intracellular signaling. This review focuses on the biochemical interactions of desmin, with a discussion of its putative functions.

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Section: Biochemical Aspectsmentioning

confidence: 84%

Desmin: molecular interactions and putative functions of the muscle intermediate filament protein

Costa

Escaleira

Cataldo

et al. 2004

Braz J Med Biol Res

120

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“…In addition, we note that desmin was also modified by phosphorylation at serine 28. Phosphorylation of several serines at the N terminus head domain of chicken desmin has been shown to inhibit the formation of intermediate filaments (44,45) and phosphorylated desmin isoforms increase in human myofibrillar myopathies (46,47). Therefore, the phosphorylation of serine 28 on desmin could be a specific marker of the altered desmin filament network in the context of cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

Muscle Creatine Kinase Deficiency Triggers Both Actin Depolymerization and Desmin Disorganization by Advanced Glycation End Products in Dilated Cardiomyopathy

Diguet

Mallat

Ladouce

et al. 2011

Journal of Biological Chemistry

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Alterations in the balance of cytoskeleton as well as energetic proteins are involved in the cardiac remodeling occurring in dilated cardiomyopathy (DCM). We used two-dimensional DIGE proteomics as a discovery approach to identify key molecular changes taking place in a temporally controlled model of DCM triggered by cardiomyocyte-specific serum response factor (SRF) knock-out in mice. We identified muscle creatine kinase (MCK) as the primary down-regulated protein followed by ␣-actin and ␣-tropomyosin down-regulation leading to a decrease of polymerized F-actin. The early response to these defects was an increase in the amount of desmin intermediate filaments and phosphorylation of the ␣B-crystallin chaperone. We found that ␣B-crystallin and desmin progressively lose their striated pattern and accumulate at the intercalated disk and the sarcolemma, respectively. We further show that desmin is a preferential target of advanced glycation end products (AGE) in mouse and human DCM. Inhibition of CK in cultured cardiomyocytes is sufficient to recapitulate both the actin depolymerization defect and the modification of desmin by AGE. Treatment with either cytochalasin D or glyoxal, a cellular AGE, indicated that both actin depolymerization and AGE contribute to desmin disorganization. Heat shock-induced phosphorylation of ␣B-crystallin provides a transient protection of desmin against glyoxal in a p38 MAPK-dependent manner. Our results show that the strong down-regulation of MCK activity contributes to F-actin instability and induces post-translational modification of ␣B-crystallin and desmin. Our results suggest that AGE may play an important role in DCM because they alter the organization of desmin filaments that normally support stress response and mitochondrial functions in cardiomyocytes.

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“…95 Weakness may or may not involve upper extremities, trunk, neck flexors and facial muscles. In disease variants marked with early onset cardiomyopathy, patients experienced dizziness, syncopal and fainting episodes associated with conduction blocks requiring a permanent pacemaker.…”

Section: Clinical Manifestations Definitions Of Desminopathymentioning

confidence: 99%

“…8,95,103 The age of disease onset was in the mid-30s and rate of progression was moderate. Muscle biopsy results were characteristic of desminopathy.…”

Section: Phenotypes Associated With Cryab Mutationsmentioning

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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Storage of phosphorylated desmin in a familial myopathy

Cited by 103 publications

References 15 publications

Desmin: molecular interactions and putative functions of the muscle intermediate filament protein

Desmin: molecular interactions and putative functions of the muscle intermediate filament protein

Muscle Creatine Kinase Deficiency Triggers Both Actin Depolymerization and Desmin Disorganization by Advanced Glycation End Products in Dilated Cardiomyopathy

Intermediate Filament Diseases: Desminopathy

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