Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle

Sugarman, Michael C.; Yamasaki, Tritia R.; Oddo, Salvatore; Echegoyen, Julio; Murphy, Michael P.; Golde, Todd E.; Jannatipour, Mehrdad; Leissring, Malcolm A.; LaFerla, Frank M.

doi:10.1073/pnas.082545599

Cited by 106 publications

(127 citation statements)

References 43 publications

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“…This was explained by Stevnes and Lowe, [18], who stated that the degenerated fibers release different inflammatory mediators that lead to mononuclear cellular infiltration. Many markers were reported as signs of muscle fiber damage and degenerative myopathies as the central located nuclei observed in this study [19,20]. The splitting of the muscle fibers might be due to the insufficient oxygen supply and metabolites exchange to the enlarged and hypertrophied fibers [17].…”

Section: The Morphometric Resultsmentioning

confidence: 99%

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

Mokhmer¹,

Saber²,

Hamouda³

et al. 2017

J Cytol Histol

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Section: The Morphometric Resultsmentioning

confidence: 99%

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

Mokhmer¹,

Saber²,

Hamouda³

et al. 2017

J Cytol Histol

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“…Abnormal increase of AβPP/Aβ appears to be an early upstream step in the IBM pathogenesis because a) AβPP/Aβ accumulation appears to precede other detected abnormalities ins-IBM muscle fibers [2], and b) several aspects of the IBM phenotype were produced in cultured normal human muscle fibers (CHMFs) after experimental long-term overexpression of AβPP [5][6][7]. Long overexpression of AβPP in muscle of transgenic mice also induced some aspects of the IBM phenotype [8][9][10]. Moreover, increased oligomerization of Aβ was associated with increased degeneration of CHMFs [11].…”

Section: Introductionmentioning

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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“…14,21,27 MaxiSorp immunoplates (Nalge Nunc, Rochester, NY) were coated with antibody against A␤1-17 (gift from Dr. William Van Nostrand) at a concentration of 25 g/l, and A␤40 and A␤42 were detected by specific horseradish peroxidase-conjugated antibody against A␤35-40 (MM32-13.1.1) or A␤35-42 (MM40-21.3.4), respectively.…”

Section: Enzyme-linked Immunosorbent Assay (Elisa) A␤ Measurementmentioning

confidence: 99%

Genetically Augmenting Aβ42 Levels in Skeletal Muscle Exacerbates Inclusion Body Myositis-Like Pathology and Motor Deficits in Transgenic Mice

Kitazawa

Green

Caccamo

et al. 2006

The American Journal of Pathology

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The pathogenic basis of inclusion body myositis (IBM), the leading muscle degenerative disease afflicting the elderly, is unknown, although the histopathological features are remarkably similar to those observed in Alzheimer's disease. One leading hypothesis is that the buildup of amyloid-␤ (A␤) peptide within selective skeletal muscle fibers contributes to the degenerative phenotype. A␤ is a small peptide derived via endoproteolysis of the amyloid precursor protein (APP). To determine the pathogenic effect of augmenting A␤42 levels in skeletal muscle, we used a genetic approach to replace the endogenous wildtype presenilin-1 (PS1) allele with the PS1 M146V allele in MCK-APP mice. Although APP transgene expression was unaltered, A␤ levels, particularly A␤42, were elevated in skeletal muscle of the double transgenic (MCK-APP/PS1) mice compared to the parental MCK-APP line. Elevated phospho-tau accumulation was found in the MCK-APP/PS1 mice, and the greater activation of GSK-3␤ and cdk5 were observed. Other IBM-like pathological features, such as inclusion bodies and inflammatory infiltrates, were more severe and prominent in the MCK-APP/PS1 mice. Motor coordination and balance were more adversely affected and manifested at an earlier age in the MCK-APP/PS1 mice. The data presented here provide experimental evidence that A␤42 plays a proximal and critical role in the muscle degenerative process. Inclusion body myositis (IBM), the most prevalent muscle disorder among the elderly, is characterized by proximal and distal skeletal muscle weakness.1-3 The clinical features of this disorder are characterized by muscle weakness and atrophy, with selective involvement of both proximal and distal muscle groups, including the quadriceps, iliopsoas, triceps, and biceps muscles. In sporadic IBM, the majority of patients usually exhibit proximal weakness, and the quadriceps are more severely affected compared to other lower limb muscles.3 In hereditary IBM, however, affected muscles may exhibit a more restricted focus. For example, the quadriceps may be selectively spared in certain autosomal recessive cases. 4,5 Histopathologically, both sporadic and hereditary IBM are characterized by atrophic muscle fibers and fibers containing rimmed vacuoles and abnormal protein aggregates, particularly amyloid-␤ (A␤), which is derived via endoproteolysis of the amyloid precursor protein (APP), and hyperphosphorylated tau. 2,6 -10 IBM and Alzheimer's disease (AD) share many pathohistological features including the buildup of aggregated proteins such as A␤ and tau. In this regard, IBM can also be considered as a proteinopathy. As in AD, the role of the A␤ peptide is unresolved, although evidence suggests that it plays an early and critical role in the muscle degeneration. IBM remains the only known condition in which A␤ accumulates pathologically outside the central nervous system, except for age-related macular degeneration.11 This distinction implicates a critical role for A␤ in the pathogenesis of IBM. A noteworthy difference between...

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Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle

Cited by 106 publications

References 43 publications

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

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

Genetically Augmenting Aβ42 Levels in Skeletal Muscle Exacerbates Inclusion Body Myositis-Like Pathology and Motor Deficits in Transgenic Mice

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