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The effects of MyD88 deficiency on disease phenotype in dysferlin-deficient A/J mice: Role of endogenous toll-like receptor (TLR) ligands

ABSTRACT: Genome wide expression study of the effect of single stranded RNA (ssRNA) in A/JOlaHsd (WT), A/J and A/J-MyD88 deficient mice. The hypothesis for this study was that endogenous TLR ligands released from the leaking dysferlin-deficient muscle fibers engage TLRs on muscle and immune cells and contribute to disease progression.These data point to a clear role for the TLR pathway in the pathogenesis of dysferlin deficiency.

ORGANISM(S): Mus musculus

PROVIDER: GSE46420 | GEO | 2013/04/27

SECONDARY ACCESSION(S): PRJNA200304

REPOSITORIES: GEO

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The effects of MyD88 deficiency on disease phenotype in dysferlin-deficient A/J mice: Role of endogenous toll-like receptor (TLR) ligands

Project description:Genome wide expression study of the effect of single stranded RNA (ssRNA) in A/JOlaHsd (WT), A/J and A/J-MyD88 deficient mice. The hypothesis for this study was that endogenous TLR ligands released from the leaking dysferlin-deficient muscle fibers engage TLRs on muscle and immune cells and contribute to disease progression.These data point to a clear role for the TLR pathway in the pathogenesis of dysferlin deficiency. Total RNA obtained from isolated tibalis anterior muscles (TA) of A/JOlaHsd (WT), A/J and A/J-MyD88 deficient mice that were subjected to 3 intramuscular injections of ssRNA over the period of 10 days compared to their contraleteral legs that were injected with saline (control).

2013-04-27 | E-GEOD-46420 | biostudies-arrayexpress

Cardiac and skeletal muscle gene expression profiles in dysferlin deficient mice

2005-07-10 | GSE2507 | GEO

Transcription profiling of skeletal and cardiac muscles in dysferlin-deficient SJL/J mice and wild type mice to understand the protective mechanisms against dysferlin deficiency in cardiac muscles.

Project description:Dysferlin is expressed in skeletal and cardiac muscle. However, dysferlin deficiency, namely limb girdle muscular dystrophy 2B (LGMD2B) and Myoshi myopathy, results in skeletal muscle weakness and spares the heart. This dichotomy could be caused by differential regulation of protective mechanisms. Therefore, we compared intraindividual mRNA expression profiles between cardiac and skeletal muscle in dysferlin-deficient SJL/J mice and normal C57BL/6 mice. Experiment Overall Design: 20 chips were analyzed. They represent 4 groups of 5 replicates each. Experiment Overall Design: The 4 groups are cardiac (LV) and skeletal muscle of normal and dysferlin deficient mice. Experiment Overall Design: Tissues from normal mice are the controls in comparison to tissues of dysferlin deficient mice.

2007-09-04 | E-GEOD-2507 | biostudies-arrayexpress

Dysferlin deficient mice proteomics

Project description:Investigation of age-dependent changes in the proteomic profile of Dysferlin-deficient mouse skeletal muscle relative to healthy muscle.

2022-01-04 | MSV000088639 | MassIVE

Dysferlin deficiency modulates the proximal-distal muscle transcriptome

Project description:By comparing the transcriptome from proximal (quadriceps femoris, QF) and distal (tibialis anterior, TA)muscle groups in dysferlin deficient mouse muscle (the SJL mutation bred onto C57BL/10 to produces C57BL/10-SJL.Dysf) with proximal and distal muscle groups from control C57BL/10 mice of an equivalent age (3-weeks old, prior to the onset of overt pathology) we aim to address the issues of muscle selectivity in this this form of muscular dystrophy. Keywords: parallel sample

2005-05-06 | GSE2629 | GEO

The effects of MyD88 deficiency on disease phenotype in dysferlin-deficient A/J mice: role of endogenous TLR ligands.

Project description:An absence of dysferlin leads to activation of innate immune receptors such as Toll-like receptors (TLRs) and skeletal muscle inflammation. Myeloid differentiation primary response gene 88 (MyD88) is a key mediator of TLR-dependent innate immune signalling. We hypothesized that endogenous TLR ligands released from the leaking dysferlin-deficient muscle fibres engage TLRs on muscle and immune cells and contribute to disease progression. To test this hypothesis, we generated and characterized dysferlin and MyD88 double-deficient mice. Double-deficient mice exhibited improved body weight, grip strength, and maximum muscle contractile force at 6-8 months of age when compared to MyD88-sufficient, dysferlin-deficient A/J mice. Double-deficient mice also showed a decrease in total fibre number, which contributed to the observed increase in the number of central nuclei/fibres. These results indicate that there was less regeneration in the double-deficient mice. We next tested the hypothesis that endogenous ligands, such as single-stranded ribonucleic acids (ssRNAs), released from damaged muscle cells bind to TLR-7/8 and perpetuate the disease progression. We found that injection of ssRNA into the skeletal muscle of pre-symptomatic mice (2 months old) resulted in a significant increase in degenerative fibres, inflammation, and regenerating fibres in A/J mice. In contrast, characteristic histological features were significantly decreased in double-deficient mice. These data point to a clear role for the TLR pathway in the pathogenesis of dysferlin deficiency and suggest that TLR-7/8 antagonists may have therapeutic value in this disease.

| S-EPMC4071457 | biostudies-literature

Assessment of the molecular consequences associated with loss of dysferlin expression in hiPSC-derived muscle cells from LGMD R2 patients.

Project description:LGMD R2 is a rare genetic disorder characterized by progressive proximal muscle weakness and wasting caused by a recessive loss of function of dysferlin, a transmembrane protein controlling plasma membrane repair in skeletal muscles. Despite major advances in biotherapies in recent years, there is currently no curative treatment available for LGMD R2, or dysferlinopathies in general. This failure can be explained in part by our lack of understanding of the functions performed by dysferlin within the muscle fiber. Indeed, despite the identification of dysferlin's role in membrane repair, intracellular vesicular trafficking or calcium homeostasis, we do not know which of these functions or combination of functions is most involved in the pathophysiological development of dysferlinopathies. It also seems highly likely that other dysferlin functions have yet to be discovered. In this aim, we generated hiPSC-derived skeletal muscle model and investigated the molecular consequences associated with loss of dysferlin expression by performing a comparative gene expression profiling between control and LGMD R2 myotubes.

2026-01-12 | GSE261832 | GEO

Transcription profiling of proximal and distal muscle groups in dysferlin-deficient mice (C57BL/10.SJL_Dysf) to understand selective pattern of muscle involvement in muscular dystrophies

Project description:By comparing the transcriptome from proximal (quadriceps femoris, QF) and distal (tibialis anterior, TA)muscle groups in dysferlin deficient mouse muscle (the SJL mutation bred onto C57BL/10 to produces C57BL/10.SJL_Dysf) with proximal and distal muscle groups from control C57BL/10 mice of an equivalent age (3-weeks old, prior to the onset of overt pathology) we aim to address the issues of muscle selectivity in this this form of muscular dystrophy.

2007-08-31 | E-GEOD-2629 | biostudies-arrayexpress

Role of annexin A2 in muscle repair

Project description:Repair of injured muscle involves repair of injured myofibers through the involvement of dysferlin and its interacting partners, including annexin. Studies with mice and patients have established that dysferlin deficit leads to chronic inflammation and adipogenic replacement of the diseased muscle. However, longitudinal analysis of annexin deficit on muscle pathology and function is lacking. Here we show that unlike annexin A1, but similar to dysferlin, lack of annexin A2 (AnxA2) causes poor myofiber repair and progressive weakening with age. However, unlike dysferlin-deficient muscle, AnxA2-deficient muscles do not exhibit chronic inflammation or adipogenic replacement. Deletion of AnxA2 in dysferlin deficient mice reduces inflammation, adipogenic replacement, and loss in muscle function caused by dysferlin deficit. These results show that: a) AnxA2 facilitates myofiber repair, b) chronic inflammation and adipogenic replacement of dysferlinopathic muscle requires AnxA2, and c) inhibiting AnxA2-mediated inflammation is a novel therapeutic avenue for dysferlinopathy.

2016-10-04 | GSE87557 | GEO

Minimal expression of dysferlin prevents development of muscular dystrophy in dysferlin exon 40a knockout mice

Project description:Dysferlin is an essential muscle membrane repair protein and autosomal recessive mutations in its gene result in progressive muscular dystrophies collectively called dysferlinopathies. We previously showed that calpain-mediated cleavage within dysferlin exon 40a releases a 72kDa C-terminal minidysferlin recruited to injured sarcolemma. In the current study, we hypothesised that knocking out exon 40a will lead to defective membrane repair and development of muscular dystrophy over time. To address this hypothesis, we created three exon 40a knockout (40aKO) mouse lines with dysferlin protein levels ranging from ~80% of wildtype (WT) in 40aKO-3, ~50% in 40aKO-2 and ~10-20% in 40aKO-1 mice. Histopathological analysis of skeletal muscles harvested from all 12-month-old 40aKO mice showed little evidence of dystrophic features seen in dysferlin-null BLAJ mice. Lipidomics analysis on 18wk old quadriceps showed that all 40aKO lines had a similar lipidomic profile to WT and distinct from BLAJs. The proteomic profile of 40aKO lines was intermediate between that of WT and BLAJs. Laser membrane damage assays showed normal membrane repair capacity in all three 40aKO lines. These results collectively indicate that ~10-20% of dysferlin protein expression is sufficient for maintenance of the lipidome and membrane repair capacity, and crucially prevents development of muscular dystrophy.

2023-03-11 | PXD035393 | Pride

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