Dataset Information

Phenotype standardization for statin-induced myotoxicity.

ABSTRACT: Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

SUBMITTER: Alfirevic A

PROVIDER: S-EPMC4172546 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Publications

Phenotype standardization for statin-induced myotoxicity.

Alfirevic A A Neely D D Armitage J J Chinoy H H Cooper R G RG Laaksonen R R Carr D F DF Bloch K M KM Fahy J J Hanson A A Yue Q-Y QY Wadelius M M Maitland-van Der Zee A H AH Voora D D Psaty B M BM Palmer C N A CN Pirmohamed M M

Clinical pharmacology and therapeutics 20140604 4

Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myop ...[more]

PMID: 24897241

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Project description:Methylmercury (MeHg) is a ubiquitous environmental contaminant and neurotoxicant that has long been known to cause a variety of motor deficits. These motor deficits have primarily been attributed to MeHg targeting of developing neurons and induction of oxidative stress and calcium dysregulation. Few studies have looked at how MeHg may be affecting fundamental signaling mechanisms in development, particularly in developing muscle. Studies in Drosophila recently revealed that MeHg perturbs embryonic muscle formation and upregulates Notch target genes, reflected predominantly by expression of the downstream transcriptional repressor Enhancer of Split mdelta [E(spl)m?]. An E(spl)m? reporter gene shows expression primarily in the myogenic domain, and both MeHg exposure and genetic upregulation of E(spl)m? can disrupt embryonic muscle development. Here, we tested the hypothesis that developing muscle is targeted by MeHg via upregulation of E(spl)m? using genetic modulation of E(spl)m? expression in combination with MeHg exposure in developing flies. Developmental MeHg exposure causes a decreased rate of eclosion that parallels gross disruption of indirect flight muscle (IFM) development. An increase in E(spl) expression across the pupal stages, with preferential E(spl)m? upregulation occurring at early (p5) stages, is also observed. E(spl)m? overexpression in myogenic lineages under the Mef2 promoter was seen to phenocopy eclosion and IFM effects of developmental MeHg exposure; whereas reduced expression of E(spl)m? shows rescue of eclosion and IFM morphology effects of MeHg exposure. No effects were seen on eclosion with E(spl)m? overexpression in neural and gut tissues. Our data indicate that muscle development is a target for MeHg and that E(spl)m? is a muscle-specific mediator of this myotoxicity. This research advances our knowledge of the target pathways that mediate susceptibility to MeHg toxicity, as well as a potential muscle development-specific role for E(spl)m?.

Dataset Information

Phenotype standardization for statin-induced myotoxicity.

Publications

Phenotype standardization for statin-induced myotoxicity.

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