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The role of TRAIL in mediating autophagy in myositis skeletal muscle: a potential nonimmune mechanism of muscle damage.

ABSTRACT: OBJECTIVE:Multinucleated cells are relatively resistant to classic apoptosis, and the factors initiating cell death and damage in myositis are not well defined. We hypothesized that nonimmune autophagic cell death may play a role in muscle fiber damage. Recent reports indicate that TRAIL may induce both NF-?B activation and autophagic cell death in other systems. We undertook this study to investigate the role of TRAIL in cell death and pathogenesis in vitro and in vivo, using myositis muscle tissues from humans and mice. METHODS:Gene expression profiling was performed in myositis patient and control muscle specimens. Immunohistochemistry analysis was performed to confirm the gene array findings. We also analyzed TRAIL-induced cell death (apoptosis and autophagy) and NF-?B activation in vitro in cultured cells. RESULTS:TRAIL was expressed predominantly in myositis muscle fibers, but not in biopsy specimens from normal or other dystrophic-diseased muscle. Autophagy markers were up-regulated in humans with myositis and in mouse models of myositis. TRAIL expression was restricted to regenerating/atrophic areas of muscle fascicles, blood vessels, and infiltrating lymphocytes. TRAIL induced NF-?B activation and I?B degradation in cultured cells that are resistant to TRAIL-induced apoptosis but that undergo autophagic cell death. CONCLUSION:Our data demonstrate that TRAIL is expressed in myositis muscle and may mediate both activation of NF-?B and autophagic cell death in myositis. Thus, this nonimmune pathway may be an attractive target for therapeutic intervention in myositis.

SUBMITTER: Alger HM

PROVIDER: S-EPMC3203318 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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The role of TRAIL in mediating autophagy in myositis skeletal muscle: a potential nonimmune mechanism of muscle damage.

Alger Heather M HM Raben Nina N Pistilli Emidio E Francia Dwight L DL Rawat Rashmi R Getnet Derese D Ghimbovschi Svetlana S Chen Yi-Wen YW Lundberg Ingrid E IE Nagaraju Kanneboyina K

Arthritis and rheumatism 20111101 11

<h4>Objective</h4>Multinucleated cells are relatively resistant to classic apoptosis, and the factors initiating cell death and damage in myositis are not well defined. We hypothesized that nonimmune autophagic cell death may play a role in muscle fiber damage. Recent reports indicate that TRAIL may induce both NF-κB activation and autophagic cell death in other systems. We undertook this study to investigate the role of TRAIL in cell death and pathogenesis in vitro and in vivo, using myositis m ...[more]

PMID: 21769834

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Project description:ObjectiveTo identify changes in skeletal muscle microRNA expression after endurance exercise and associate the identified microRNAs with mRNA and protein expression to disease-specific pathways in polymyositis (PM) and dermatomyositis (DM) patients.MethodsFollowing a parallel clinical trial design, patients with probable PM or DM, exercising less than once a week, and on stable medication for at least one month were randomized into two groups at Karolinska University Hospital: a 12-week endurance exercise group (n = 12) or a non-exercised control group (n = 11). Using an Affymetrix microarray, microRNA expression was determined in paired muscle biopsies taken before and after the exercise intervention from 3 patients in each group. Ingenuity pathway analysis with a microRNA target filter was used to identify microRNA transcript targets. These targets were investigated at the mRNA (microarray) and protein (mass spectrometry) levels in patients.ResultsEndurance exercise altered 39 microRNAs. The microRNAs with increased expression were predicted to target transcripts involved in inflammatory processes, metabolism, and muscle atrophy. Further, these target transcripts had an associated decrease in mRNA expression in exercised patients. In particular, a decrease in the NF-κB regulator IKBKB was associated with an increase in its target microRNA (miR-196b). At the protein level, there was an increase in mitochondrial proteins (AK3, HIBADH), which were associated with a decrease in microRNAs that were predicted to regulate their expression.ConclusionImprovement in disease phenotype after exercise is associated with increasing microRNAs that target and downregulate immune processes at the transcript level, as well as decreasing microRNAs that target and upregulate mitochondrial content at the protein level. Therefore, microRNAs may improve disease by decreasing immune responses and increasing mitochondrial biogenesis.Trial registrationClinicalTrials.gov NCT01184625.

Dataset Information

The role of TRAIL in mediating autophagy in myositis skeletal muscle: a potential nonimmune mechanism of muscle damage.

Publications

The role of TRAIL in mediating autophagy in myositis skeletal muscle: a potential nonimmune mechanism of muscle damage.

Similar Datasets

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