p62/SQSTM1 is overexpressed and prominently accumulated in inclusions of sporadic inclusion-body myositis muscle fibers, and can help differentiating it from polymyositis and dermatomyositis

Department of Neurology, USC Neuromuscular Center, Good Samaritan Hospital, University of Southern California Keck School of Medicine, Los Angeles, CA 90017-1912, USA.
Acta Neuropathologica (Impact Factor: 9.78). 07/2009; 118(3):407-13. DOI: 10.1007/s00401-009-0564-6
Source: PubMed

ABSTRACT p62, also known as sequestosome1, is a shuttle protein transporting polyubiquitinated proteins for both the proteasomal and lysosomal degradation. p62 is an integral component of inclusions in brains of various neurodegenerative disorders, including Alzheimer disease (AD) neurofibrillary tangles (NFTs) and Lewy bodies in Parkinson disease. In AD brain, the p62 localized in NFTs is associated with phosphorylated tau (p-tau). Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease associated with aging, and its muscle tissue has several phenotypic similarities to AD brain. Abnormal accumulation of intracellular multiprotein inclusions, containing p-tau in the form of paired helical filaments, amyloid-beta, and several other "Alzheimer-characteristic proteins", is a characteristic feature of the s-IBM muscle fiber phenotype. Diminished proteasomal and lysosomal protein degradation appear to play an important role in the formation of intra-muscle-fiber inclusions. We now report that: (1) in s-IBM muscle fibers, p62 protein is increased on both the protein and the mRNA levels, and it is strongly accumulated within, and as a dense peripheral shell surrounding, p-tau containing inclusions, by both the light- and electron-microscopy. Accordingly, our studies provide a new, reliable, and simple molecular marker of p-tau inclusions in s-IBM muscle fibers. The prominent p62 immunohistochemical positivity and pattern diagnostically distinguish s-IBM from polymyositis and dermatomyositis. (2) In normal cultured human muscle fibers, experimental inhibition of either proteasomal or lysosomal protein degradation caused substantial increase of p62, suggesting that similar in vivo mechanisms might contribute to the p62 increase in s-IBM muscle fibers.

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Available from: Chiara Terracciano, Aug 06, 2015
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    • "Eleven patients had received a treatment with either low-dose steroids alone (n = 5) or combined with azathrioprine or methotrexate (n = 6) before biopsy. The definitive diagnosis of s-IBM was based on established clinico-pathological criteria [5] [22] and sarcoplasmic immunoreactivity for b-amyloid, phosphorylated tau, p62 [23] or TDP-43 protein [24] within >1% of muscle fibers. For comparison with other inflammatory myopathies, muscle biopsies from patients referred to the Reference Center for Neuromuscular Diseases, Institut de Myologie, Hô pital Pitié-Salpetrière who displayed treatment-responsive Table 1 Demographic data of patients. "
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    ABSTRACT: Muscle repair relies on coordinated activation and differentiation of satellite cells, a process that is unable to counterbalance progressive degeneration in sporadic inclusion body myositis (s-IBM). To explore features of myo regeneration, the expression of myogenic regulatory factors Pax7, MyoD and Myogenin and markers of regenerating fibers was analyzed by immunohistochemistry in s-IBM muscle compared with polymyositis, dermatomyositis, muscular dystrophy and age-matched controls. In addition, the capillary density and number of interstitial CD34(+) hematopoietic progenitor cells was determined by double-immunoflourescence staining. Satellite cells and regenerating fibers were significantly increased in s-IBM similar to other inflammatory myopathies and correlated with the intensity of inflammation (R>0.428). Expression of MyoD, visualizing activated satellite cells and proliferating myoblasts, was lower in s-IBM compared to polymyosits. In contrast, Myogenin a marker of myogenic cell differentiation was strongly up-regulated in s-IBM muscle. The microvascular architecture in s-IBM was distorted, although the capillary density was normal. Notably, CD34(+) hematopoietic cells were significantly increased in the interstitial compartment. Our findings indicate profound myo-endothelial remodeling of s-IBM muscle concomitant to inflammation. An altered expression of myogenic regulatory factors involved in satellite cell activation and differentiation, however, might reflect perturbations of muscle repair in s-IBM.
    Neuromuscular Disorders 10/2012; 23(1). DOI:10.1016/j.nmd.2012.09.003 · 3.13 Impact Factor
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    • "p62 and TDP-43 immunoreactive fibers were observed in all presumed d s-IBM cases and in 37 and 31% of p s-IBM, respectively. That means that: 1) a posteriori all d s-IBM patients were well classified and finally, by the presence of PHF evidenced by p62 (Nogalska et al., 2009) fulfill all the Griggs criteria for d s-IBM. The percentage was increased to 42% by adding the cases of p s-IBM re-classified with each marker. "
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    ABSTRACT: Sporadic inclusion body myositis (s-IBM) is characterized histologically by the association of concomitant inflammatory and degenerative processes. We evaluated the sensitivity and specificity of different markers of the degenerative process in order to refine the histological diagnosis. We performed an immunohistochemical study with antibodies directed against ubiquitin, amyloid-beta precursor protein (AbetaPP), amyloid-beta (Abeta), SMI-31, SMI-310, Tar-DNA binding protein-43 (TDP-43) and p62 on s-IBM and control muscle biopsies. Based on conventional stains 36 patients with characteristic clinical features of s-IBM were subclassified as presumed definite s-IBM (d s-IBM, n = 17) or possible s-IBM (p s-IBM, n = 19) according to the presence or absence of vacuolated muscle fibers. Immunohistochemically, TDP-43 and p62 were the most sensitive markers, accumulating in all d s-IBM and in 31% and 37%, respectively, of the p s-IBM cases and thus enabling reclassification of these cases as d s-IBM. We recommend using TDP-43 and p62 antibodies in the histological diagnosis workup of s-IBM. The specificity of these markers has to be further validated in prospective series.
    Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases 10/2011; 30(2):103-8.
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    • "The features of protein aggregation, abnormal mitochondria and distension of endo/sarcoplasmic reticulum that are typical of many acquired and genetic muscle diseases suggest an impairment, more than an exacerbation, of autophagic flux. For instance, protein aggregates that are positive for ubiquitin and p62/SQSTM1 proteins have been recently described in muscle of patients affected by sporadic Inclusion Body Myositis as well as in different tissuespecific autophagy knockout mice [25] [26] [27]. To clarify the role of basal autophagy we have generated two conditional knockout mice for the critical Atg7 gene to block autophagy specifically in skeletal muscle [28]. "
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    ABSTRACT: Muscle mass represents 40-50% of the human body and, in mammals, is one of the most important sites for the control of metabolism. Moreover, during catabolic conditions, muscle proteins are mobilized to sustain gluconeogenesis in the liver and to provide alternative energy substrates for organs. However, excessive protein degradation in the skeletal muscle is detrimental for the economy of the body and it can lead to death. The ubiquitin-proteasome and autophagy-lysosome systems are the major proteolytic pathways of the cell and are coordinately activated in atrophying muscles. However, the role and regulation of the autophagic pathway in skeletal muscle is still largely unknown. This review will focus on autophagy and discuss its beneficial or detrimental role for the maintenance of muscle mass.
    FEBS letters 04/2010; 584(7):1411-6. DOI:10.1016/j.febslet.2010.01.056 · 3.34 Impact Factor
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