Inflammatory Muscle Diseases

Young, Pablo; Finn, Bárbara C; Reisin, Ricardo

doi:10.1056/nejmc1506827

Cited by 139 publications

(39 citation statements)

References 57 publications

(151 reference statements)

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“…Histologically, IBM biopsies often display cytoplasmic protein “inclusions,” rimmed vacuoles, mitochondrial abnormalities, increased MHC type I expression, and infiltrating CD8 + T cells [22]. The molecular pathogenesis of IBM remains unclear and is controversial, but likely involves both inflammatory and myodegenerative processes [5, 14]. However, unlike in other inflammatory myopathies (i.e.…”

Section: Introductionmentioning

confidence: 99%

Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

Amici

Pinal‐Fernandez

Mázala

et al. 2017

acta neuropathol commun

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Sporadic inclusion body myositis (IBM) is the most common primary myopathy in the elderly, but its pathoetiology is still unclear. Perturbed myocellular calcium (Ca2+) homeostasis can exacerbate many of the factors proposed to mediate muscle degeneration in IBM, such as mitochondrial dysfunction, protein aggregation, and endoplasmic reticulum stress. Ca2+ dysregulation may plausibly be initiated in IBM by immune-mediated membrane damage and/or abnormally accumulating proteins, but no studies to date have investigated Ca2+ regulation in IBM patients. We first investigated protein expression via immunoblot in muscle biopsies from IBM, dermatomyositis, and non-myositis control patients, identifying several differentially expressed Ca2+-regulatory proteins in IBM. Next, we investigated the Ca2+-signaling transcriptome by RNA-seq, finding 54 of 183 (29.5%) genes from an unbiased list differentially expressed in IBM vs. controls. Using an established statistical approach to relate genes with causal transcription networks, Ca2+ abundance was considered a significant upstream regulator of observed whole-transcriptome changes. Post-hoc analyses of Ca2+-regulatory mRNA and protein data indicated a lower protein to transcript ratio in IBM vs. controls, which we hypothesized may relate to increased Ca2+-dependent proteolysis and decreased protein translation. Supporting this hypothesis, we observed robust (4-fold) elevation in the autolytic activation of a Ca2+-activated protease, calpain-1, as well as increased signaling for translational attenuation (eIF2α phosphorylation) downstream of the unfolded protein response. Finally, in IBM samples we observed mRNA and protein under-expression of calpain-3, the skeletal muscle-specific calpain, which broadly supports proper Ca2+ homeostasis. Together, these data provide novel insight into mechanisms by which intracellular Ca2+ regulation is perturbed in IBM and offer evidence of pathological downstream effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0427-7) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

Amici

Pinal‐Fernandez

Mázala

et al. 2017

acta neuropathol commun

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Section: Introductionmentioning

confidence: 99%

“…Dermatomyositis (DM) is a rare systemic autoimmune myopathy associated with high functional disability [1]. Although skeletal striated muscle tissue is the main target in DM, its involvement is often accompanied by tissue and/or organ impairment as a result of systemic inflammatory processes [1]. The cause could be multifactorial involving interactions between genetic and environmental risk factors and, in this aspect, several trigger factors (i.e., drugs, infections, hormones, occupational exposures, vaccines, among others) would act on predisposed patients, favoring changes in the immunoregulatory mechanism responsible for the DM manifestations [1].…”

Section: Introductionmentioning

confidence: 99%

Tofacitinib as a Treatment for Refractory Dermatomyositis: A Case Report

Shinjo¹,

Souza²

2020

OJRA

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In very scarce case reports and case series, tofacitinib has been a therapeutic alternative for dermatomyositis. To corroborate the literature, we described a refractory dermatomyositis that had a good outcome with tofacitinib. Case Report: An adult female patient presented with definite dermatomyositis and with refractoriness to high doses of intravenous and oral glucocorticoids, intravenous human immunoglobulin, several immunosuppressive drugs (methotrexate, azathioprine, and leflunomide) and two previous immunobiological drugs (rituximab and abatacept). However, the patient had a good outcome with tofacitinib. Conclusions: Tofacitinib appears to be a promising alternative therapy for refractory dermatomyositis.

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“…Polymyositis [4, 5], dermatomyositis [6, 7], and rheumatoid arthritis [3, 8] are typical autoimmune diseases in modern society. For example, polymyositis is a chronic illness featuring progressive muscle weakness with periods of increased symptoms, including inflammation of the muscles or associated tissues [9, 10]. So far, the major understanding of pathophysiology in autoimmune diseases has been the irregular immunity and inflammation of immune cells [11, 12].…”

Section: Introductionmentioning

confidence: 99%

DEPTOR-mTOR Signaling Is Critical for Lipid Metabolism and Inflammation Homeostasis of Lymphocytes in Human PBMC Culture

Xie

Liang

Yang

et al. 2017

Journal of Immunology Research

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Abnormal immune response of the body against substances and tissues causes autoimmune diseases, such as polymyositis, dermatomyositis, and rheumatoid arthritis. Irregular lipid metabolism and inflammation may be a significant cause of autoimmune diseases. Although much progress has been made, mechanisms of initiation and proceeding of metabolic and inflammatory regulation in autoimmune disease have not been well-defined. And novel markers for the detection and therapy of autoimmune disease are urgent. mTOR signaling is a central regulator of extracellular metabolic and inflammatory processes, while DEP domain-containing mTOR-interacting protein (DEPTOR) is a natural inhibitor of mTOR. Here, we report that overexpression of DEPTOR reduces mTORC1 activity in lymphocytes of human peripheral blood mononuclear cells (PBMCs). Combination of DEPTOR overexpression and mTORC2/AKT inhibitors effectively inhibits lipogenesis and inflammation in lymphocytes of PBMC culture. Moreover, DEPTOR knockdown activates mTORC1 and increases lipogenesis and inflammations. Our findings provide a deep insight into the relationship between lipid metabolism and inflammations via DEPTOR-mTOR pathway and imply that DEPTOR-mTOR in lymphocytes of PBMC culture has the potential to be as biomarkers for the detection and therapies of autoimmune diseases.

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Inflammatory Muscle Diseases

Cited by 139 publications

References 57 publications

Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

Tofacitinib as a Treatment for Refractory Dermatomyositis: A Case Report

DEPTOR-mTOR Signaling Is Critical for Lipid Metabolism and Inflammation Homeostasis of Lymphocytes in Human PBMC Culture

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