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1.
Subcell Biochem ; 104: 485-501, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38963497

RESUMO

Valosin-containing protein (VCP), also known as p97, is an evolutionarily conserved AAA+ ATPase essential for cellular homeostasis. Cooperating with different sets of cofactors, VCP is involved in multiple cellular processes through either the ubiquitin-proteasome system (UPS) or the autophagy/lysosomal route. Pathogenic mutations frequently found at the interface between the NTD domain and D1 ATPase domain have been shown to cause malfunction of VCP, leading to degenerative disorders including the inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and cancers. Therefore, VCP has been considered as a potential therapeutic target for neurodegeneration and cancer. Most of previous studies found VCP predominantly exists and functions as a hexamer, which unfolds and extracts ubiquitinated substrates from protein complexes for degradation. However, recent studies have characterized a new VCP dodecameric state and revealed a controlling mechanism of VCP oligomeric states mediated by the D2 domain nucleotide occupancy. Here, we summarize our recent knowledge on VCP oligomerization, regulation, and potential implications of VCP in cellular function and pathogenic progression.


Assuntos
Proteína com Valosina , Proteína com Valosina/metabolismo , Proteína com Valosina/genética , Proteína com Valosina/química , Humanos , Multimerização Proteica , Animais , Mutação , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/química , Osteíte Deformante/genética , Osteíte Deformante/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/química , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/metabolismo , Distrofia Muscular do Cíngulo dos Membros
2.
Int J Mol Sci ; 25(12)2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38928252

RESUMO

Inclusion body myositis (IBM) is a slowly progressive disorder belonging to the idiopathic inflammatory myopathies, and it represents the most common adult-onset acquired myopathy. The main clinical features include proximal or distal muscular asymmetric weakness, with major involvement of long finger flexors and knee extensors. The main histological findings are the presence of fiber infiltrations, rimmed vacuoles, and amyloid inclusions. The etiopathogenesis is a challenge because both environmental and genetic factors are implicated in muscle degeneration and a distinction has been made previously between sporadic and hereditary forms. Here, we describe an Italian patient affected with a hereditary form of IBM with onset in his mid-forties. Next-generation sequencing analysis disclosed a heterozygous mutation c.76C>T (p.Pro26Ser) in the PDZ motif of the LDB3/ZASP gene, a mutation already described in a family with a late-onset myopathy and highly heterogenous degree of skeletal muscle weakness. In the proband's muscle biopsy, the expression of ZASP, myotilin, and desmin were increased. In our family, in addition to the earlier age of onset, the clinical picture is even more peculiar given the evidence, in one of the affected family members, of complete ophthalmoplegia in the vertical gaze. These findings help extend our knowledge of the clinical and genetic background associated with inclusion body myopathic disorders.


Assuntos
Proteínas com Domínio LIM , Miosite de Corpos de Inclusão , Linhagem , Humanos , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/patologia , Masculino , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Músculo Esquelético/metabolismo , Mutação , Adulto
3.
Clin Exp Rheumatol ; 42(2): 445-453, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38436356

RESUMO

Inclusion body myositis (IBM) is a progressive, debilitating muscle disease commonly encountered in patients over the age of 50. IBM typically presents with asymmetric, painless, progressive weakness and atrophy of deep finger flexors and/or quadriceps muscle. Many patients with IBM develop dysphagia. However, atypical presentations of IBM with isolated dysphagia, asymptomatic hyper-CKemia, foot drop, proximal weakness, axial weakness, and facial diplegia have been reported. Other acquired and some inherited disorders may present similar to IBM, and this list gets more expansive when considering atypical presentations. In general, disease progression of IBM leads to loss of hand function and impaired ambulation, and most IBM patients become wheelchair dependent within 13-15 years of disease onset. Hence, IBM impacts negatively patients' quality of life and reduces longevity compared to the general population. Acknowledging the complete clinical spectrum of IBM presentation and excluding mimics would shorten the time to diagnosis, lead to prompt initiation of supportive management and avoid unproven therapy. Ongoing advanced phase studies in IBM provide hope that a therapy may soon be available. Therefore, an added potential benefit of early diagnosis would be prompt initiation of disease-modifying therapy once available.


Assuntos
Transtornos de Deglutição , Miosite de Corpos de Inclusão , Miosite , Humanos , Miosite de Corpos de Inclusão/diagnóstico , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/terapia , Qualidade de Vida , Debilidade Muscular/etiologia
4.
Muscle Nerve ; 69(6): 699-707, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38551101

RESUMO

INTRODUCTION/AIMS: VCP multisystem proteinopathy 1 (MSP1), encompassing inclusion body myopathy (IBM), Paget's disease of bone (PDB) and frontotemporal dementia (FTD) (IBMPFD), features progressive muscle weakness, fatty infiltration, and disorganized bone structure in Pagetic bones. The aim of this study is to utilize dual-energy x-ray absorptiometry (DXA) parameters to examine it as a biomarker of muscle and bone disease in MSP1. METHODS: DXA scans were obtained in 28 patients to assess body composition parameters (bone mineral density [BMD], T-score, total fat, and lean mass) across different groups: total VCP disease (n = 19), including myopathy without Paget's ("myopathy"; n = 12) and myopathy with Paget's ("Paget"; n = 7), and unaffected first-degree relatives serving as controls (n = 6). RESULTS: In the VCP disease group, significant declines in left hip BMD and Z-scores were noted versus the control group (p ≤ .03). The VCP disease group showed decreased whole body lean mass % (p = .04), and increased total body fat % (p = .04) compared to controls. Subgroup comparisons indicated osteopenia in 33.3% and osteoporosis in 8.3% of the myopathy group, with 14.3% exhibiting osteopenia in the Paget group. Moreover, the Paget group displayed higher lumbar L1-L4 T-score values than the myopathy group. DISCUSSION: In MSP1, DXA revealed reduced bone and lean mass, and increased fat mass. These DXA insights could aid in monitoring disease progression of muscle loss and secondary osteopenia/osteoporosis in MSP1, providing value both clinically and in clinical research.


Assuntos
Absorciometria de Fóton , Densidade Óssea , Distrofia Muscular do Cíngulo dos Membros , Miosite de Corpos de Inclusão , Osteíte Deformante , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Transversais , Idoso , Miosite de Corpos de Inclusão/diagnóstico por imagem , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/genética , Osteíte Deformante/diagnóstico por imagem , Osteíte Deformante/genética , Osteíte Deformante/complicações , Adulto , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Composição Corporal , Proteína com Valosina/genética , Adenosina Trifosfatases/genética
5.
Sci Rep ; 14(1): 5917, 2024 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-38467645

RESUMO

Multisystem Proteinopathy 1 (MSP1) disease is a rare genetic disorder caused by mutations in the Valosin-Containing Protein (VCP) gene with clinical features of inclusion body myopathy (IBM), frontotemporal dementia (FTD), and Paget's disease of bone (PDB). We performed bone scan imaging in twelve patients (6 females, 6 males) with confirmed VCP gene mutation six (50%) of which has myopathy alone, four (33%) with both PDB and myopathy, and two (15%) were presymptomatic carriers. We aim to characterize the PDB in diagnosed individuals, and potentially identify PDB in the myopathy and presymptomatic groups. Interestingly, two patients with previously undiagnosed PDB had positive diagnostic findings on the bone scan and subsequent radiograph imaging. Among the individuals with PDB, increased radiotracer uptake of the affected bones were of typical distribution as seen in conventional PDB and those reported in other MSP1 cohorts which are the thoracic spine and ribs (75%), pelvis (75%), shoulder (75%) and calvarium (15%). Overall, we show that technetium-99m bone scans done at regular intervals are a sensitive screening tool in patients with MSP1 associated VCP variants at risk for PDB. However, diagnostic confirmation should be coupled with clinical history, biochemical analysis, and skeletal radiographs to facilitate early treatment and prevention complications, acknowledging its limited specificity.


Assuntos
Demência Frontotemporal , Distrofia Muscular do Cíngulo dos Membros , Miosite de Corpos de Inclusão , Osteíte Deformante , Masculino , Feminino , Humanos , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Proteína com Valosina/genética , Proteínas de Ciclo Celular/genética , Osteíte Deformante/diagnóstico por imagem , Osteíte Deformante/genética , Proteína 1 de Superfície de Merozoito/genética , Tomografia Computadorizada por Raios X , Mutação , Miosite de Corpos de Inclusão/diagnóstico por imagem , Miosite de Corpos de Inclusão/genética
6.
Int J Mol Sci ; 25(5)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38473988

RESUMO

Sporadic inclusion body myositis (sIBM) is the most common muscle disease of older people and is clinically characterized by slowly progressive asymmetrical muscle weakness, predominantly affecting the quadriceps, deep finger flexors, and foot extensors. At present, there are no enduring treatments for this relentless disease that eventually leads to severe disability and wheelchair dependency. Although sIBM is considered a rare muscle disorder, its prevalence is certainly higher as the disease is often undiagnosed or misdiagnosed. The histopathological phenotype of sIBM muscle biopsy includes muscle fiber degeneration and endomysial lymphocytic infiltrates that mainly consist of cytotoxic CD8+ T cells surrounding nonnecrotic muscle fibers expressing MHCI. Muscle fiber degeneration is characterized by vacuolization and the accumulation of congophilic misfolded multi-protein aggregates, mainly in their non-vacuolated cytoplasm. Many players have been identified in sIBM pathogenesis, including environmental factors, autoimmunity, abnormalities of protein transcription and processing, the accumulation of several toxic proteins, the impairment of autophagy and the ubiquitin-proteasome system, oxidative and nitrative stress, endoplasmic reticulum stress, myonuclear degeneration, and mitochondrial dysfunction. Aging has also been proposed as a contributor to the disease. However, the interplay between these processes and the primary event that leads to the coexistence of autoimmune and degenerative changes is still under debate. Here, we outline our current understanding of disease pathogenesis, focusing on degenerative mechanisms, and discuss the possible involvement of aging.


Assuntos
Miosite de Corpos de Inclusão , Humanos , Idoso , Miosite de Corpos de Inclusão/genética , Linfócitos T CD8-Positivos/metabolismo , Inflamação/complicações , Envelhecimento , Proteínas , Miocárdio/metabolismo
7.
J Autoimmun ; 142: 103150, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38043487

RESUMO

OBJECTIVES: Inclusion body myositis (IBM) is a progressive inflammatory-degenerative muscle disease of older individuals, with some patients producing anti-cytosolic 5'-nucleotidase 1A (NT5C1A, aka cN1A) antibodies. Human Leukocyte Antigens (HLA) is the highest genetic risk factor for developing IBM. In this study, we aimed to further define the contribution of HLA alleles to IBM and the production of anti-cN1A antibodies. METHODS: We HLA haplotyped a Western Australian cohort of 113 Caucasian IBM patients and 112 ethnically matched controls using Illumina next-generation sequencing. Allele frequency analysis and amino acid alignments were performed using the Genentech/MiDAS bioinformatics package. Allele frequencies were compared using Fisher's exact test. Age at onset analysis was performed using the ggstatsplot package. All analysis was carried out in RStudio version 1.4.1717. RESULTS: Our findings validated the independent association of HLA-DRB1*03:01:01 with IBM and attributed the risk to an arginine residue in position 74 within the DRß1 protein. Conversely, DRB4*01:01:01 and DQA1*01:02:01 were found to have protective effects; the carriers of DRB1*03:01:01 that did not possess these alleles had a fourteenfold increased risk of developing IBM over the general Caucasian population. Furthermore, patients with the abovementioned genotype developed symptoms on average five years earlier than patients without. We did not find any HLA associations with anti-cN1A antibody production. CONCLUSIONS: High-resolution HLA sequencing more precisely characterised the alleles associated with IBM and defined a haplotype linked to earlier disease onset. Identification of the critical amino acid residue by advanced biostatistical analysis of immunogenetics data offers mechanistic insights and future directions into uncovering IBM aetiopathogenesis.


Assuntos
Miosite de Corpos de Inclusão , Miosite , Humanos , Miosite de Corpos de Inclusão/genética , Genótipo , Haplótipos , Arginina , Austrália , Antígenos HLA , Cadeias HLA-DRB1/genética , Alelos
8.
Neuromuscul Disord ; 34: 89-94, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38159460

RESUMO

Valosin-containing protein (VCP) pathogenic variants are the most common cause of multisystem proteinopathy presenting with inclusion body myopathy, amyotrophic lateral sclerosis/frontotemporal dementia, and Paget disease of bone in isolation or in combination. We report a patient manifesting with adolescent-onset myopathy caused by a novel heterozygous VCP variant (c.467G > T, p.Gly156Val). The myopathy manifested asymmetrically in lower limbs and extended to proximal, axial, and upper limb muscles, with loss of ambulation at age 35. Creatine kinase value was normal. Alkaline phosphatase was elevated. Electromyography detected mixed low amplitude, short duration and high amplitude, long duration motor unit potentials. Muscle biopsy showed features of inclusion body myopathy, which in combination with newly diagnosed Paget disease of bone, supported the VCP variant pathogenicity. In conclusion, VCP-multisystem proteinopathy is not only a disease of adulthood but can have a pediatric onset and should be considered in differential diagnosis of neuromuscular weakness in the pediatric population.


Assuntos
Doenças Musculares , Miosite de Corpos de Inclusão , Osteíte Deformante , Deficiências na Proteostase , Adolescente , Adulto , Criança , Humanos , Proteínas de Ciclo Celular/genética , Mutação/genética , Miosite de Corpos de Inclusão/diagnóstico , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/patologia , Osteíte Deformante/diagnóstico , Osteíte Deformante/genética , Osteíte Deformante/patologia , Proteína com Valosina/genética
9.
Int J Mol Sci ; 24(13)2023 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-37446317

RESUMO

BACKGROUND: Sporadic inclusion body myositis (s-IBM) represents a unique disease within idiopathic inflammatory myopathies with a dual myodegenerative-autoimmune physiopathology and a lack of an efficacious treatment. Circulating miRNA expression could expand our knowledge of s-IBM patho-mechanisms and provide new potential disease biomarkers. To evaluate the expression of selected pre-amplified miRNAs in the serum of s-IBM patients compared to those of a sex- and age-matched healthy control group, we enrolled 14 consecutive s-IBM patients and 8 sex- and age-matched healthy controls. By using two different normalization approaches, we found one downregulated and three upregulated miRNAs. hsa-miR-192-5p was significantly downregulated, while hsa-miR-372-3p was found to be upregulated more in the s-IBM patients compared to the level of the controls. The other two miRNAs had a very low expression levels (raw Ct data > 29). hsa-miR-192-5p and hsa-miR-372-3p were found to be significantly dysregulated in the serum of s-IBM patients. These miRNAs are involved in differentiation and regeneration processes, thus possibly reflecting pathological mechanisms in s-IBM muscles and potentially representing disease biomarkers.


Assuntos
MicroRNA Circulante , MicroRNAs , Miosite de Corpos de Inclusão , Miosite , Humanos , MicroRNA Circulante/genética , Miosite de Corpos de Inclusão/genética , MicroRNAs/metabolismo , Biomarcadores
10.
J Neurol ; 270(11): 5483-5492, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37498322

RESUMO

INTRODUCTION: Inclusion body myositis (IBM), an inflammatory myopathy with progressive weakness without efficient treatment, typically presents after 45 years of age and younger patients are sparsely studied. METHODS: In a population-based study during a 33-year period, 142 patients with IBM were identified in western Sweden. Six patients fell outside the European Neuromuscular Centre 2011 criteria for IBM due to young age at symptom onset, verified by a muscle biopsy < 50 years of age. These were defined as early-onset IBM and included in this study. Medical records, muscle strength, comorbidities, muscle biopsies, and nuclear- and mitochondrial DNA were examined and compared with patients with IBM and age matched controls from the same population. RESULTS: The median age at symptom onset was 36 (range 34-45) years and at diagnosis 43 (range 38-58) years. Four patients were deceased at a median age of 59 (range 50-75) years. The median survival from diagnosis was 14 (range 10-18) years. The prevalence December 31 2017 was 1.2 per million inhabitants and the mean incidence 0.12 patients per million inhabitants and year. The mean decline in quadriceps strength ± 1 standard deviation was 1.21 ± 0.2 Newton or 0.91 ± 0.2% per month and correlated to time from diagnosis (p < 0.001). Five patients had swallowing difficulties. All patients displayed mitochondrial changes in muscle including cytochrome c oxidase deficiency and the mitochondrial DNA mutation load was high. CONCLUSIONS: Early-onset IBM is a severe disease, causing progressive muscle weakness, high muscle mitochondrial DNA mutation load and a reduced cumulative survival in young and middle-aged individuals.


Assuntos
Miosite de Corpos de Inclusão , Miosite , Pessoa de Meia-Idade , Humanos , Adulto , Idoso , Miosite de Corpos de Inclusão/diagnóstico , Miosite de Corpos de Inclusão/epidemiologia , Miosite de Corpos de Inclusão/genética , Miosite/complicações , Debilidade Muscular/epidemiologia , Debilidade Muscular/etiologia , Músculos/patologia , DNA Mitocondrial
11.
J Neurol ; 270(9): 4434-4443, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37280376

RESUMO

OBJECTIVE: The molecular characteristics of sporadic inclusion body myositis (sIBM) have been intensively studied, and specific patterns on the cellular, protein and RNA level have emerged. However, these characteristics have not been studied in the context of HIV-associated IBM (HIV-IBM). In this study, we compared clinical, histopathological, and transcriptomic patterns of sIBM and HIV-IBM. METHODS: In this cross-sectional study, we compared patients with HIV-IBM and sIBM based on clinical and morphological features as well as gene expression levels of specific T-cell markers in skeletal muscle biopsy samples. Non-disease individuals served as controls (NDC). Cell counts for immunohistochemistry and gene expression profiles for quantitative PCR were used as primary outcomes. RESULTS: 14 muscle biopsy samples (7 HIV-IBM, 7 sIBM) of patients and 6 biopsy samples from NDC were included. Clinically, HIV-IBM patients showed a significantly lower age of onset and a shorter period between symptom onset and muscle biopsy. Histomorphologically, HIV-IBM patients showed no KLRG1+ or CD57+ cells, while the number of PD1+ cells did not differ significantly between the two groups. All markers were shown to be significantly upregulated at gene expression level with no significant difference between the IBM subgroups. CONCLUSION: Despite HIV-IBM and sIBM sharing important clinical, histopathological, and transcriptomic signatures, the presence of KLRG1+ cells discriminated sIBM from HIV-IBM. This may be explained by longer disease duration and subsequent T-cell stimulation in sIBM. Thus, the presence of TEMRA cells is characteristic for sIBM, but not a prerequisite for the development of IBM in HIV+ patients.


Assuntos
Infecções por HIV , Miosite de Corpos de Inclusão , Humanos , Miosite de Corpos de Inclusão/genética , Estudos Transversais , Proteínas , Linfócitos T/patologia , Infecções por HIV/complicações , Infecções por HIV/patologia , Músculo Esquelético/patologia
12.
Front Immunol ; 14: 1161476, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37153570

RESUMO

Background: Inclusion body myositis (IBM) is a slowly progressive inflammatory myopathy that typically affects the quadriceps and finger flexors. Sjögren's syndrome (SS), an autoimmune disorder characterized by lymphocytic infiltration of exocrine glands has been reported to share common genetic and autoimmune pathways with IBM. However, the exact mechanism underlying their commonality remains unclear. In this study, we investigated the common pathological mechanisms involved in both SS and IBM using a bioinformatic approach. Methods: IBM and SS gene expression profiles were obtained from the Gene Expression Omnibus (GEO). SS and IBM coexpression modules were identified using weighted gene coexpression network analysis (WGCNA), and differentially expressed gene (DEG) analysis was applied to identify their shared DEGs. The hidden biological pathways were revealed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Furthermore, protein-protein interaction (PPI) networks, cluster analyses, and hub shared gene identification were conducted. The expression of hub genes was validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). We then analyzed immune cell abundance patterns in SS and IBM using single-sample gene set enrichment analysis (ssGSEA) and investigated their association with hub genes. Finally, NetworkAnalyst was used to construct a common transcription factor (TF)-gene network. Results: Using WGCNA, we found that 172 intersecting genes were closely related to viral infection and antigen processing/presentation. Based on DEG analysis, 29 shared genes were found to be upregulated and enriched in similar biological pathways. By intersecting the top 20 potential hub genes from the WGCNA and DEG sets, three shared hub genes (PSMB9, CD74, and HLA-F) were derived and validated to be active transcripts, which all exhibited diagnostic values for SS and IBM. Furthermore, ssGSEA showed similar infiltration profiles in IBM and SS, and the hub genes were positively correlated with the abundance of immune cells. Ultimately, two TFs (HDGF and WRNIP1) were identified as possible key TFs. Conclusion: Our study identified that IBM shares common immunologic and transcriptional pathways with SS, such as viral infection and antigen processing/presentation. Furthermore, both IBM and SS have almost identical immune infiltration microenvironments, indicating similar immune responses may contribute to their association.


Assuntos
Doenças Autoimunes , Miosite de Corpos de Inclusão , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/genética , Miosite de Corpos de Inclusão/genética , Apresentação de Antígeno , Biologia Computacional
13.
Immunohorizons ; 7(5): 310-322, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-37171806

RESUMO

Inclusion body myositis (IBM) is an autoimmune and degenerative disorder of skeletal muscle. The B cell infiltrates in IBM muscle tissue are predominantly fully differentiated Ab-secreting plasma cells, with scarce naive or memory B cells. The role of this infiltrate in the disease pathology is not well understood. To better define the humoral response in IBM, we used adaptive immune receptor repertoire sequencing, of human-derived specimens, to generate large BCR repertoire libraries from IBM muscle biopsies and compared them to those generated from dermatomyositis, polymyositis, and circulating CD27+ memory B cells, derived from healthy controls and Ab-secreting cells collected following vaccination. The repertoire properties of the IBM infiltrate included the following: clones that equaled or exceeded the highly clonal vaccine-associated Ab-secreting cell repertoire in size; reduced somatic mutation selection pressure in the CDRs and framework regions; and usage of class-switched IgG and IgA isotypes, with a minor population of IgM-expressing cells. The IBM IgM-expressing population revealed unique features, including an elevated somatic mutation frequency and distinct CDR3 physicochemical properties. These findings demonstrate that some of IBM muscle BCR repertoire characteristics are distinct from dermatomyositis and polymyositis and circulating Ag-experienced subsets, suggesting that it may form through selection by disease-specific Ags.


Assuntos
Dermatomiosite , Miosite de Corpos de Inclusão , Polimiosite , Humanos , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/patologia , Dermatomiosite/patologia , Plasmócitos , Músculo Esquelético , Polimiosite/patologia , Receptores de Antígenos de Linfócitos B/genética , Imunoglobulina M
14.
J Cachexia Sarcopenia Muscle ; 14(2): 964-977, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36860172

RESUMO

BACKGROUND: Inclusion body myositis (IBM) is an inflammatory myopathy clinically characterized by proximal and distal muscle weakness, with inflammatory infiltrates, rimmed vacuoles and mitochondrial changes in muscle histopathology. There is scarce knowledge on IBM aetiology, and non-established biomarkers or effective treatments are available, partly due to the lack of validated disease models. METHODS: We have performed transcriptomics and functional validation of IBM muscle pathological hallmarks in fibroblasts from IBM patients (n = 14) and healthy controls (n = 12), paired by age and sex. The results comprise an mRNA-seq, together with functional inflammatory, autophagy, mitochondrial and metabolic changes between patients and controls. RESULTS: Gene expression profile of IBM vs control fibroblasts revealed 778 differentially expressed genes (P-value adj < 0.05) related to inflammation, mitochondria, cell cycle regulation and metabolism. Functionally, an increased inflammatory profile was observed in IBM fibroblasts with higher supernatant cytokine secretion (three-fold increase). Autophagy was reduced considering basal protein mediators (18.4% reduced), time-course autophagosome formation (LC3BII 39% reduced, P-value < 0.05), and autophagosome microscopic evaluation. Mitochondria displayed reduced genetic content (by 33.9%, P-value < 0.05) and function (30.2%-decrease in respiration, 45.6%-decline in enzymatic activity (P-value < 0.001), 14.3%-higher oxidative stress, 135.2%-increased antioxidant defence (P-value < 0.05), 11.6%-reduced mitochondrial membrane potential (P-value < 0.05) and 42.8%-reduced mitochondrial elongation (P-value < 0.05)). In accordance, at the metabolite level, organic acid showed a 1.8-fold change increase, with conserved amino acid profile. Correlating to disease evolution, oxidative stress and inflammation emerge as potential markers of prognosis. CONCLUSIONS: These findings confirm the presence of molecular disturbances in peripheral tissues from IBM patients and prompt patients' derived fibroblasts as a promising disease model, which may eventually be exported to other neuromuscular disorders. We additionally identify new molecular players in IBM associated with disease progression, setting the path to deepen in disease aetiology, in the identification of novel biomarkers or in the standardization of biomimetic platforms to assay new therapeutic strategies for preclinical studies.


Assuntos
Miosite de Corpos de Inclusão , Miosite , Humanos , Miosite de Corpos de Inclusão/diagnóstico , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/metabolismo , Músculos/metabolismo , Inflamação/patologia , Biomarcadores/metabolismo
15.
Clin Exp Rheumatol ; 41(2): 340-347, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36861744

RESUMO

OBJECTIVES: Sporadic inclusion body myositis (IBM) is the most common acquired myopathy in those aged above 50. It is classically heralded by weakness in the long finger flexors and quadriceps. The aim of this article is to describe five atypical cases of IBM, outlining two potential emerging clinical subsets of the disease. METHODS: We reviewed relevant clinical documentation and pertinent investigations for five patients with IBM. RESULTS: The first phenotype we describe is young-onset IBM in two patients who had symptoms since their early thirties. The literature supports that IBM can rarely present in this age range or younger. We describe a second phenotype in three middle-aged women who developed early bilateral facial weakness at presentation in tandem with dysphagia and bulbar impairment followed by respiratory failure requiring non-invasive ventilation (NIV). Within this group, two patients were noted to have macroglossia, another possible rare feature of IBM. CONCLUSIONS: Despite the classical phenotype described within the literature IBM can present in a heterogenous fashion. It is important to recognise IBM in younger patients and investigate for specific associations. The described pattern of facial diplegia, severe dysphagia, bulbar dysfunction and respiratory failure in female IBM patients requires further characterisation. Patients with this clinical pattern may require more complex and supportive management. Macroglossia is a potentially under recognised feature of IBM. The presence of macroglossia in IBM warrants further study, as its presence may lead to unnecessary investigations and delay diagnosis.


Assuntos
Transtornos de Deglutição , Macroglossia , Miosite de Corpos de Inclusão , Feminino , Humanos , Miosite de Corpos de Inclusão/diagnóstico , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/terapia , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/etiologia , Fenótipo
16.
Genes (Basel) ; 14(3)2023 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-36980948

RESUMO

Valosin-containing protein (VCP) gene mutations have been associated with a rare autosomal dominant, adult-onset progressive disease known as multisystem proteinopathy 1 (MSP1), or inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), (IBMPFD), and amyotrophic lateral sclerosis (ALS). We report the clinical and genetic analysis findings in five patients, three from the same family, with novel VCP gene variants: NM_007126.5 c.1106T>C (p.I369T), c.478G>A (p.A160T), and c.760A>T (p.I254F), associated with cardinal MSP1 manifestations including myopathy, PDB, and FTD. Our report adds to the spectrum of heterozygous pathogenic variants found in the VCP gene and the high degree of clinical heterogeneity. This case series prompts increased awareness and early consideration of MSP1 in the differential diagnosis of myopathies and/or PDB, dementia, or ALS to improve the diagnosis and early management of clinical symptoms.


Assuntos
Esclerose Lateral Amiotrófica , Demência Frontotemporal , Miosite de Corpos de Inclusão , Osteíte Deformante , Adulto , Humanos , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Esclerose Lateral Amiotrófica/genética , Osteíte Deformante/genética , Osteíte Deformante/patologia , Proteína com Valosina/genética , Proteínas de Ciclo Celular/genética , Proteína 1 de Superfície de Merozoito , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/patologia
17.
Autoimmun Rev ; 22(5): 103308, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36822387

RESUMO

We investigated the relationship between oxidative stress and inflammatory myopathies. We searched in the current literature the role of mitochondria and respiratory chain defects as sources of oxidative stress and reactive oxygen species production that led to muscle weakness and fatigue. Different molecules and pathways contribute to redox milieu, reactive oxygen species generation, accumulation of misfolded and carbonylated proteins that lose their ability to fulfil cellular activities. Small peptides and physical techniques proved, in mice models, to reduce oxidative stress. We focused on inclusion body myositis, as a major expression of myopathy related to oxidative stress, where mitochondrial abnormalities are causative agents as well. We described the effect of physical exercise in inclusion body myositis that showed to increase strength and to reduce beta amyloid accumulation with subsequent improvement of the mitochondrial functions. We illustrated the influence of epigenetic control on the immune system by non-coding genetic material in the interaction between oxidative stress and inflammatory myopathies.


Assuntos
Miosite de Corpos de Inclusão , Miosite , Humanos , Animais , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Miosite de Corpos de Inclusão/genética , Transporte de Elétrons , Estresse Oxidativo , Miosite/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo
19.
J Neurol ; 270(3): 1787-1797, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36399165

RESUMO

Inclusion body myositis (IBM) belongs to the group of idiopathic inflammatory myopathies and is characterized by a slowly progressive disease course with asymmetric muscle weakness of predominantly the finger flexors and knee extensors. The disease leads to severe disability and most patients lose ambulation due to lack of curative or disease-modifying treatment options. Despite some genes reported to be associated with hereditary IBM (a distinct group of conditions), data on the genetic susceptibility of sporadic IBM are very limited. This review gives an overview of the disease and focuses on the current genetic knowledge and potential therapeutic implications.


Assuntos
Miosite de Corpos de Inclusão , Miosite , Humanos , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/terapia , Progressão da Doença
20.
Ann Clin Transl Neurol ; 9(10): 1602-1615, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36107781

RESUMO

OBJECTIVE: Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy in patients older than 50 years of age. sIBM is hardly responds to any immunosuppressing theraphies, and its pathophysiology remains elusive. This study aims to explore pathogenic pathways underlying sIBM and identify novel therapeutic targets using metabolomic and transcriptomic analyses. METHODS: In this retrospective observational study, we analyzed biopsied muscle samples from 14 sIBM patients and six non-diseased subjects to identify metabolic profiles. Frozen muscle samples were used to measure metabolites with cation and anion modes of capillary electrophoresis time of flight mass spectrometry. We validated the metabolic pathway altered in muscles of sIBM patients through RNA sequencing and histopathological studies. RESULTS: A total of 198 metabolites were identified. Metabolomic and transcriptomic analyses identified specific metabolite changes in sIBM muscle samples. The pathways of histamine biosynthesis and certain glycosaminoglycan biosynthesis were upregulated in sIBM patients, whereas those of carnitine metabolism and creatine metabolism were downregulated. Histopathological examination showed infiltration of mast cells and deposition of chondroitin sulfate in skeletal muscle samples, supporting the results of metabolomic and transcriptomic analyses. INTERPRETATION: We identified alterations of several metabolic pathways in muscle samples of sIBM patients. These results suggest that mast cells, chondroitin sulfate biosynthesis, carnitine, and creatine play roles in sIBM pathophysiology.


Assuntos
Miosite de Corpos de Inclusão , Carnitina/metabolismo , Sulfatos de Condroitina/metabolismo , Creatina/genética , Creatina/metabolismo , Perfilação da Expressão Gênica , Histamina/metabolismo , Humanos , Metaboloma , Músculo Esquelético , Miosite de Corpos de Inclusão/genética
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