Endoplasmic Reticulum Stress and Unfolded Protein Response in Inclusion Body Myositis Muscle

Vattemi, Gaetano; Engel, W. King; McFerrin, Janis; Askanas, Valerie

doi:10.1016/s0002-9440(10)63089-1

Cited by 172 publications

(185 citation statements)

References 30 publications

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“…Three days after transfer, experimental and control (non-AβPP-overexpressing) cultures were treated with 1μM epoxomicin (Biomol Research Laboratories, Plymouth Meeting, PA), an irreversible proteasome inhibitor [22]. 24 hours thereafter, the cultures were processed for light-microscopic immunocytochemistry, immunoblotting, and combined immunoprecipitation/immunoblotting, as described [4][5][6][7]11,23,24].…”

Section: Cultured Human Muscle Fibers (Chmfs)mentioning

confidence: 99%

“…These were performed as described [5,7,11,23,24]. In brief, 10μg of protein were loaded onto 12% NuPAGE gels (Invitrogen, Grand Island, NY), electrophoresed in MES-SDS NuPAGE buffer, transferred to nitrocellulose membranes, and immuno-probed with mouse monoclonal antibodies against αBC, diluted 1:1000.…”

Section: Immunoblotsmentioning

confidence: 99%

“…To evaluate whether, in AβPP-overexpressing ("AβPP+") CHMFs, αBC physically associates with AβPP and Aβ oligomers, we performed a 2-stage-combined immunoprecipitationimmunoblot technique, as described [23,24]. In brief, 100 μg of total muscle protein was immunoprecipitated in precipitation-buffer containing either 5 μg of 6E10 antibody against AβPP/Aβ (Signet, Dedham, MA), or 5 μg of antibody against αBC.…”

Section: Combined Immunoprecipitation-immunoblottingmentioning

confidence: 99%

“…To evaluate if in s-IBM muscle fibers αBC physically associates with AβPP and/or Aβ, a combined immunoprecipitation-immunoblot technique was performed, essentially as above and as described [4,[23][24][25]. In brief, 100 μg of total muscle protein from s-IBM and control muscle biopsies were individually immunoprecipitated in precipitation buffer containing 5 μg of anti-αBC antibody, The immunoprecipitates were electrophoresed: a) on 12% NuPAGE gel in MES-SDS NuPAGE buffer to visualize Aβ oligomers, and b) on 4-12% NuPAGE gel in MOPS-SDS NuPAGE buffer to visualize AβPP.…”

Section: Combined Immunoprecipitation-immunoblot Proceduresmentioning

confidence: 99%

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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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Section: Cultured Human Muscle Fibers (Chmfs)mentioning

confidence: 99%

Section: Immunoblotsmentioning

confidence: 99%

Section: Combined Immunoprecipitation-immunoblottingmentioning

confidence: 99%

Section: Combined Immunoprecipitation-immunoblot Proceduresmentioning

confidence: 99%

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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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“…Studies in cultured muscle have shown that the accumulation of these proteins ultimately leads to myofibrillar dysfunction and subsequent death (18 -20). IBM skeletal muscle biopsies reveal the accumulation of additional proteins, including the ␤-amyloid-converting enzyme (BACE-1 and 2, ␤-secretase) (21), the serine/threonine kinase cdk-5 (22), proteins related to endoplasmic reticulum stress and the unfolded protein response (23), and notably, increased ubiquitin levels (24). The accumulation of ubiquitin in affected IBM muscle has raised the likelihood that alterations in proteasomal function could play a part in the etiology of this disorder.…”

mentioning

confidence: 99%

Parkin Protects against Mitochondrial Toxins and β-Amyloid Accumulation in Skeletal Muscle Cells

Rosen

Veereshwarayya

Moussa

et al. 2006

Journal of Biological Chemistry

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Mutations in the ubiquitin ligase-encoding Parkin gene have been implicated in the pathogenesis of autosomal recessive Parkinson disease. Outside of the central nervous system, Parkin is prominently expressed in skeletal muscle. We have found accumulations of Parkin protein in skeletal muscle biopsies taken from patients with inclusion body myositis, a degenerative disorder in which intramyofiber accumulations of the ␤-amyloid peptide are pathognomonic. In comparing primary cultures of skeletal muscle derived from parkin knock-out and wild-type mice, we have found the absence of parkin to result in greater sensitivity to mitochondrial stressors rotenone and carbonyl cyanide 3-chlorophenylhydrazone, without any alteration in sensitivity to calcium ionophore or hydrogen peroxide. Utilizing viral expression constructs coding for the Alzheimer disease and inclusion body myositis-linked ␤-amyloid precursor protein and for its metabolic byproducts A␤42 and C100, we found that parkin knock-out muscle cells are also more sensitive to the toxic effects of intracellular A␤. We also constructed a lentiviral system to overexpress wild-type Parkin and have shown that boosting the levels of parkin expression in normal skeletal muscle cultures provides substantial protection against both mitochondrial toxins and overexpressed ␤-amyloid. Correspondingly, exogenous Parkin significantly lowered A␤ levels. These data support the hypothesis that in myocytes parkin has dual properties in the maintenance of skeletal muscle mitochondrial homeostasis and in the regulation of A␤ levels. The Parkin protein is considered an E33 ubiquitin ligase and when mutated has been linked to the development of autosomal recessive Parkinson disease (1-3). In overexpression (or in cellular) models it functions to modify specific target proteins by ubiquitination, earmarking them for proteasomal degradation (3). Putative targets of Parkin include, among others, Pael-R (Parkin-associated endothelin-like receptor) (4), synphilin-1 (5), a modified form of ␣-synuclein (6), CDCrel1 (7), and p38/JTV-1, an aminoacyl-tRNA synthetase cofactor (8). Previous reports have indicated that the cellular stress response promotes the formation of a complex between Parkin, the chaperone Hsp70, the C terminus of Hsc70 interacting protein CHIP, and Pael-R (9). Recently, Parkin has also been shown to interact with the ␣4 subunit of the 19 S proteasome, although the latter does not appear to serve as a substrate for parkin-directed ubiquitination (10). Substantial accumulations of Parkin are found associated with ␣-synuclein and ubiquitin bearing Lewy bodies in Parkinson disease and dementia with Lewy bodies (11), suggesting a role in the pathologic sequestration of proteins in these disorders. Although parkin mRNA is expressed throughout the central nervous system, it is also prominently expressed in skeletal and cardiac muscle, tissues with sustained levels of protein turnover (1).Although Parkin can be found in both cytosolic and membrane-associated compartments of the cel...

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Pathogenesis of Sporadic Inclusion‐Body Myositis: Role of Aging and Muscle‐Fiber Degeneration, and Accumulation of the Same Proteins as in Alzheimer and Parkinson Brains

Askanas

Engel

Nogalska

2011

Muscle Aging, Inclusion‐Body Myositis and Myopathies

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Endoplasmic Reticulum Stress and Unfolded Protein Response in Inclusion Body Myositis Muscle

Cited by 172 publications

References 30 publications

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

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

Parkin Protects against Mitochondrial Toxins and β-Amyloid Accumulation in Skeletal Muscle Cells

Pathogenesis of Sporadic Inclusion‐Body Myositis: Role of Aging and Muscle‐Fiber Degeneration, and Accumulation of the Same Proteins as in Alzheimer and Parkinson Brains

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