Muscle fiber dysfunction contributes to weakness in inclusion body myositis

Lassche, Saskia; Rietveld, Anke; Heerschap, Arend; Hees, Hieronymus W. van; Hopman, Maria T. E.; Voermans, Nicol C.; Saris, Christiaan G J; Engelen, B.G.M. van; Ottenheijm, Coen A.C.

doi:10.1016/j.nmd.2019.03.001

Cited by 5 publications

(6 citation statements)

References 40 publications

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“…The molecular changes underlying muscle weakness remain unclear in IMNM. Lassche et.al conducted an experiment on contractile function in IBM and found that the reduced formation of attached actin-myosin cross-bridges may lead to muscle ber weakness [19]. A study on nemaline myopathy with de nite mutations also revealed impaired actin-myosin interaction causing decreased muscle ber force [20].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis of Gene Expression Profiles of Immune-mediated Necrotizing Myopathy

Shi

Wang

Zhang

et al. 2021

Preprint

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Background: Immune-mediated necrotizing myopathy (IMNM) is a type of autoimmune myopathy with limited therapeutic measures. This study aims to elucidate the potential biomarkers and investigate the underlying mechanisms in IMNM. Materials and Methods: Microarray datasets in GSE128470 and GSE39454 were obtained from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were filtrated by limma package in R statistical software. Functional enrichment analyses were performed using DAVID online tools. STRING database was used to construct protein‑protein interaction (PPI) networks. The module analysis and hub genes validation were performed using Cytoscape software. Results: Integrated analysis of two databases revealed 160 co-expressed DEGs in IMNM, including 80 downregulated genes and 80 upregulated genes. GO enrichment analysis revealed that sarcomere is the most significantly enriched GO term within the DEGs. KEGG pathway enrichment analysis revealed significant enrichment pathways in cancer. A PPI network consisting of 115 nodes and 205 edges were constructed and top 20 hub genes were identified. Two key modules from the network were identified. Eight hub genes in module 1 (MYH3, MYH7B, MYH8, MYL5, MYBPH, ACTC1, YNNT 2 and MYOG) are tightly associated with skeletal muscle construction. Seven hub genes in module 2 (C1QA, TYROBP, MS4A6A, RNASE6, FCGR2A, FCER1G and LAPTM5) mainly take part in immune response. Conclusions: Our research indicated that cancer-related pathways, skeletal muscle construction pathways and immune-mediated pathways might participate in the development of IMNM. Identified hub genes may serve as potential biomarkers or targets for early diagnosis.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis of Gene Expression Profiles of Immune-mediated Necrotizing Myopathy

Shi

Wang

Zhang

et al. 2021

Preprint

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“…30 Single muscle fiber calcium sensitivity of force was intact in muscle biopsies from patients with inclusion body myositis, an acquired muscle disease with marked inflammation and fatty infiltration. 31 However, these fibers also had reduced specific force due to myosin loss, which may prohibit compensatory changes in calcium sensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…30 Reduced muscle fiber specific force is also found in myotonic dystrophy, a multisystem disorder caused by a repeat expansion of the DMPK gene, and in inclusion body myositis, an inflammatory and degenerative acquired muscle disease. 31,32 In contrast, single muscle fiber specific force in FSHD is intact even in severely affected tissue with marked fatty infiltration. This indicates that muscle weakness in FSHD does not occur through a primary effect of DUX4 on muscle fiber contractility.…”

Section: Discussionmentioning

confidence: 99%

Preserved single muscle fiber specific force in facioscapulohumeral muscular dystrophy

et al. 2020

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ObjectiveTo investigate single muscle fiber contractile performance in muscle biopsies from patients with facioscapulohumeral muscular dystrophy (FSHD), one of the most common hereditary muscle disorders.MethodsWe collected 50 muscle biopsies (26 vastus lateralis, 24 tibialis anterior) from 14 patients with genetically confirmed FSHD and 12 healthy controls. Single muscle fibers (n = 547) were isolated for contractile measurements. Titin content and titin phosphorylation were examined in vastus lateralis muscle biopsies.ResultsSingle muscle fiber specific force was intact at saturating and physiologic calcium concentrations in all FSHD biopsies, with (FSHDFAT) and without (FSHDNORMAL) fatty infiltration, compared to healthy controls. Myofilament calcium sensitivity of force is increased in single muscle fibers obtained from FSHD muscle biopsies with increased fatty infiltration, but not in FSHD muscle biopsies without fatty infiltration (pCa50: 5.77–5.80 in healthy controls, 5.74–5.83 in FSHDNORMAL, and 5.86–5.90 in FSHDFAT single muscle fibers). Cross-bridge cycling kinetics at saturating calcium concentrations and myofilament cooperativity did not differ from healthy controls. Development of single muscle fiber passive tension was changed in all FSHD vastus lateralis and in FSHDFAT tibialis anterior, resulting in increased fiber stiffness. Titin content was increased in FSHD vastus lateralis biopsies; however, titin phosphorylation did not differ from healthy controls.ConclusionMuscle weakness in patients with FSHD is not caused by reduced specific force of individual muscle fibers, even in severely affected tissue with marked fatty infiltration of muscle tissue.

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“… 12 , 13 , 14 , 15 , 16 More recent studies have incorporated quantitative MRI techniques, such as muscle fat fraction (FF) and T 2 mapping, 17 with some exploring longitudinal changes. 18 , 19 , 20 , 21 , 22 Because repeated biopsies for monitoring disease progression are unrealistic, quantitative MRI and magnetic resonance spectroscopy (MRS) are now commonly used in many follow‐up studies of neuromuscular diseases to non‐invasively assess both acute and chronic pathological changes. The ultimate goal is to use these objective MRI/S‐based quantitative biomarkers as surrogate outcome measures in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

“…Typically, MRI protocols consist of qualitative T 1 and fat‐suppressed T 2 ‐weighted MRI to evaluate muscle fat replacement, muscle atrophy, and changes in intramuscular water distribution due to active muscle damage, especially inflammation 12–16 . More recent studies have incorporated quantitative MRI techniques, such as muscle fat fraction (FF) and T 2 mapping, 17 with some exploring longitudinal changes 18–22 . Because repeated biopsies for monitoring disease progression are unrealistic, quantitative MRI and magnetic resonance spectroscopy (MRS) are now commonly used in many follow‐up studies of neuromuscular diseases to non‐invasively assess both acute and chronic pathological changes.…”

Section: Introductionmentioning

confidence: 99%

Effect of sirolimus on muscle in inclusion body myositis observed with magnetic resonance imaging and spectroscopy

Reyngoudt,

Baudin,

Caldas de Almeida Araújo

et al. 2024

J cachexia sarcopenia muscle

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BackgroundFinding sensitive clinical outcome measures has become crucial in natural history studies and therapeutic trials of neuromuscular disorders. Here, we focus on 1‐year longitudinal data from quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31P MRS) in a placebo‐controlled study of sirolimus for inclusion body myositis (IBM), also examining their links to functional, strength, and clinical parameters in lower limb muscles.MethodsQuantitative MRI and 31P MRS data were collected at 3 T from a single site, involving 44 patients (22 on placebo, 22 on sirolimus) at baseline and year‐1, and 21 healthy controls. Assessments included fat fraction (FF), contractile cross‐sectional area (cCSA), and water T2 in global leg and thigh segments, muscle groups, individual muscles, as well as 31P MRS indices in quadriceps or triceps surae. Analyses covered patient‐control comparisons, annual change assessments via standard t‐tests and linear mixed models, calculation of standardized response means (SRM), and exploration of correlations between MRI, 31P MRS, functional, strength, and clinical parameters.ResultsThe quadriceps and gastrocnemius medialis muscles had the highest FF values, displaying notable heterogeneity and asymmetry, particularly in the quadriceps. In the placebo group, the median 1‐year FF increase in the quadriceps was 3.2% (P < 0.001), whereas in the sirolimus group, it was 0.7% (P = 0.033). Both groups experienced a significant decrease in cCSA in the quadriceps after 1 year (P < 0.001), with median changes of 12.6% for the placebo group and 5.5% for the sirolimus group. Differences in FF and cCSA changes between the two groups were significant (P < 0.001). SRM values for FF and cCSA were 1.3 and 1.4 in the placebo group and 0.5 and 0.8 in the sirolimus group, respectively. Water T2 values were highest in the quadriceps muscles of both groups, significantly exceeding control values in both groups (P < 0.001) and were higher in the placebo group than in the sirolimus group. After treatment, water T2 increased significantly only in the sirolimus group's quadriceps (P < 0.01). Multiple 31P MRS indices were abnormal in patients compared to controls and remained unchanged after treatment. Significant correlations were identified between baseline water T2 and FF at baseline and the change in FF (P < 0.001). Additionally, significant correlations were observed between FF, cCSA, water T2, and functional and strength outcome measures.ConclusionsThis study has demonstrated that quantitative MRI/31P MRS can discern measurable differences between placebo and sirolimus‐treated IBM patients, offering promise for future therapeutic trials in idiopathic inflammatory myopathies such as IBM.

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Muscle fiber dysfunction contributes to weakness in inclusion body myositis

Cited by 5 publications

References 40 publications

Bioinformatics Analysis of Gene Expression Profiles of Immune-mediated Necrotizing Myopathy

Bioinformatics Analysis of Gene Expression Profiles of Immune-mediated Necrotizing Myopathy

Preserved single muscle fiber specific force in facioscapulohumeral muscular dystrophy

Effect of sirolimus on muscle in inclusion body myositis observed with magnetic resonance imaging and spectroscopy

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