Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy

Sanbe, Atsushi; Osińska, Hanna; Villa, Chet; Gulick, James; Klevitsky, Raisa; Glabe, Charles G.; Kayed, Rakez; Robbins, Jeffrey

doi:10.1073/pnas.0503324102

Cited by 102 publications

(146 citation statements)

References 39 publications

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“…Earlier studies of DRC animal models showed that the desmin aggregates and sarcomere disarray accompany and are partially responsible for impairment of cardiomyocyte contractility,58, 59 but these ultrastructural changes do not lead to cardiomyocyte cell death by themselves 58. Our data support the hypothesis that aberrant mitochondrial fission is likely involved in mitochondrial dysfunction and the apoptotic cell death associated with desminopathy.…”

Section: Discussionsupporting

confidence: 85%

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: Discussionsupporting

confidence: 85%

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

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

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“…Our studies of cultured human muscle fibers bearing the transthyretin Val122Ile mutation and overexpressing AβPP indicated that increased muscle fiber degeneration is associated with increased Aβ oligomerization [11]. Of interest is a recent study related to cultured cardiomyocytes which experimentally expressed both αBC bearing the R120G mutation, causing desmin-related myopathy [30], and a toxic amyloidogenic peptide PQ81 [31]. Those cardiomyocytes had pronounced aggresome formation but, interestingly, inhibition of the aggresome formation through additional expression of the wild αBC led to increased accumulation of PQ81 amyloidoligomers and increased cellular toxicity [31].…”

Section: Discussionmentioning

confidence: 98%

“…Of interest is a recent study related to cultured cardiomyocytes which experimentally expressed both αBC bearing the R120G mutation, causing desmin-related myopathy [30], and a toxic amyloidogenic peptide PQ81 [31]. Those cardiomyocytes had pronounced aggresome formation but, interestingly, inhibition of the aggresome formation through additional expression of the wild αBC led to increased accumulation of PQ81 amyloidoligomers and increased cellular toxicity [31]. That study suggests that, while a mutated αBC causes aggregation of a toxic amyloidogenic protein, prevention of aggresome formation by maintaining amyloidogenic protein in the form of oligomers was associated with increased toxicity [31].…”

Section: Discussionmentioning

confidence: 99%

AβPP-overexpression and proteasome inhibition increase αB-crystallin in cultured human muscle: Relevance to inclusion-body myositis

Wójcik

Engel

McFerrin

et al. 2006

Neuromuscular Disorders

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Amyloid-β precursor protein (AβPP) and its fragment amyloid-β (Aβ) are increased in s-IBM muscle fibers and appear to play an important role in the pathogenic cascade. αB-crystallin (αBC) was shown immunohistochemically to be accumulated in s-IBM muscle fibers, but the stressor(s) influencing αBC accumulation was not identified. We now demonstrate, using our experimental IBM model based on genetic overexpression of AβPP into normal culture human muscle fibers, that: 1) AβPP overexpression increased αBC 3.7-fold (p= 0.025); 2) additional inhibition of proteasome with epoxomicin increased αBC 7-fold (p=0.002); and 3) αBC physically associated with AβPP and Aβ oligomers. We also show that in biopsied s-IBM muscle fibers, αBC was similarly increased 3-fold (p=0.025) and physically associated with AβPP and Aβ oligomers. We propose that increased AβPP is a stressor increasing αBC expression in s-IBM muscle fibers. Determining the consequences of αBC association with Aβ oligomers could have clinical therapeutic relevance.

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“…12,90 Aggregation of amyloid-like material was recently demonstrated to be a typical feature of many human cardiomyopathies, especially those caused by mutations in CRYAB. 91 Physiologically, the inclusion of misfolded proteins into aggregates was proposed to be a protective mechanism in alphaB-crystallinopathy, 92 linking desminopathy to a broad class of conformational neurodegenerative diseases. Remarkably, desmin knock-out and transgenic mice show less severe pathology as compared to the CRYAB transgenic mice.…”

Section: Role Of Alphab-crystallinmentioning

confidence: 99%

Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

107

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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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Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy

Cited by 102 publications

References 39 publications

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

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

AβPP-overexpression and proteasome inhibition increase αB-crystallin in cultured human muscle: Relevance to inclusion-body myositis

Intermediate Filament Diseases: Desminopathy

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