Overexpression of autophagic proteins in the skeletal muscle of sporadic inclusion body myositis

Girolamo, Francesco; Lia, Annamaria; Amati, A; Strippoli, Maurizio; Coppola, Cristiana; Virgintino, Daniela; Roncali, Luisa; Toscano, Antonio; Serlenga, L; Trojano, María

doi:10.1111/nan.12040

Cited by 32 publications

(27 citation statements)

References 71 publications

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“…Impaired autophagosome maturation with consequent accumulation of multiprotein aggregates is considered a key factor in the myofiber degeneration and muscle weakness characteristic of sIBM [8]–[10]. However, it is unclear whether the autophagic pathway is also altered in other IIMs [36].…”

Section: Discussionmentioning

confidence: 99%

“…Since autophagy has such a large range of physiological functions, it is unsurprising that its dysregulation contributes to several human diseases, including cardiac dysfunction, diabetes, neurodegenerative disorders (Huntington’s, Alzheimer’s and Parkinson’s diseases), cancer, and autoinflammatory/autoimmune diseases [7], including sporadic inclusion body myositis (sIBM) [8]–[10], in which it seems to be responsible for the accumulation of the multiple protein aggregates characteristic of the muscle fibers of this disease [8]. The mechanisms of autophagy dysregulation in sIBM are unknown, and clear descriptions of autophagic processes in other idiopathic inflammatory myopathies (IIMs), specifically polymyositis (PM), dermatomyositis (DM) and juvenile dermatomyositis (JDM) are also lacking.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy, Inflammation and Innate Immunity in Inflammatory Myopathies

et al. 2014

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Autophagy has a large range of physiological functions and its dysregulation contributes to several human disorders, including autoinflammatory/autoimmune diseases such as inflammatory myopathies (IIMs). In order to better understand the pathogenetic mechanisms of these muscular disorders, we sought to define the role of autophagic processes and their relation with the innate immune system in the three main subtypes of IIM, specifically sporadic inclusion body myositis (sIBM), polymyositis (PM), dermatomyositis (DM) and juvenile dermatomyositis (JDM). We found that although the mRNA transcript levels of the autophagy-related genes BECN1, ATG5 and FBXO32 were similar in IIM and controls, autophagy activation in all IIM subgroups was suggested by immunoblotting results and confirmed by immunofluorescence. TLR4 and TLR3, two potent inducers of autophagy, were highly increased in IIM, with TLR4 transcripts significantly more expressed in PM and DM than in JDM, sIBM and controls, and TLR3 transcripts highly up-regulated in all IIM subgroups compared to controls. Co-localization between autophagic marker, LC3, and TLR4 and TLR3 was observed not only in sIBM but also in PM, DM and JDM muscle tissues. Furthermore, a highly association with the autophagic processes was observed in all IIM subgroups also for some TLR4 ligands, endogenous and bacterial HSP60, other than the high-mobility group box 1 (HMGB1). These findings indicate that autophagic processes are active not only in sIBM but also in PM, DM and JDM, probably in response to an exogenous or endogenous ‘danger signal’. However, autophagic activation and regulation, and also interaction with the innate immune system, differ in each type of IIM. Better understanding of these differences may lead to new therapies for the different IIM types.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autophagy, Inflammation and Innate Immunity in Inflammatory Myopathies

et al. 2014

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“…More recently, studies have shown the presence of betaamyloid and tau deposits, as well as accumulation of several other proteins known to be involved in other neurodegenerative diseases, such as TDP-43. Other studies have also shown accumulation of autophagy-related proteins, such as LC3 and p62 [21][22][23]. Although more research needs to be done, these proteins may prove useful both in diagnosing and understanding the pathology of IBM.…”

Section: Inclusion Body Myositismentioning

confidence: 94%

Myositis Mimics

Michelle

Mammen

2015

Curr Rheumatol Rep

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Patients with autoimmune myositis typically present with muscle weakness, elevated serum levels of muscle enzymes, and abnormal muscle biopsies. However, patients with other acquired myopathies or genetic muscle diseases may have remarkably similar presentations. Making the correct diagnosis of another muscle disease can prevent these patients from being exposed to the risks of immunosuppressive medications, which benefit those with myositis, but not those with other types of muscle disease. Here, we review some of the most common acquired and inherited muscle diseases that can mimic autoimmune myositis, including inclusion body myositis, limb girdle muscular dystrophies, metabolic myopathies, mitochondrial myopathies, and endocrine myopathies. We emphasize aspects of the medical history, physical exam, laboratory evaluation, and muscle biopsy analysis that can help clinicians distinguish myositis mimics from true autoimmune myositis.

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“…A more recent immunohistochemistry study reports overexpression of the autophagy proteins ATG5, microtubule‐associated protein light chain 3 (LC3) and Beclin‐1 in IBM muscle biopsies. Interestingly, lymphocytic infiltrates were predominantly found surrounding Beclin‐1 + myofibers 261. Recently, components of chaperone‐mediated autophagy were identified to be increased in IBM as well 262.…”

Section: Degenerative Pathomechanisms In Ibmmentioning

confidence: 99%

Immune and myodegenerative pathomechanisms in inclusion body myositis

Keller

Schmidt

Lünemann

2017

Ann Clin Transl Neurol

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Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM.

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Overexpression of autophagic proteins in the skeletal muscle of sporadic inclusion body myositis

Abstract: The overexpression of autophagy markers linked to the decreased clearance of misfolded proteins, including SMI-31, and rimmed vacuoles accumulation may exhaust cellular resources and lead to cell death.

Cited by 32 publications

References 71 publications

Autophagy, Inflammation and Innate Immunity in Inflammatory Myopathies

Autophagy, Inflammation and Innate Immunity in Inflammatory Myopathies

Myositis Mimics

Immune and myodegenerative pathomechanisms in inclusion body myositis

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