A model of statin-induced myopathy has been developed using Drosophila. Statins, which reduce production of low-density lipoprotein cholesterol by the liver, are commonly prescribed for treatment of atherosclerotic cardiovascular disease. However, statin-induced myopathy is a frequent side effect; statin-associated muscle symptoms are reported by 10% to 25% of patients receiving statin therapy and contribute to high discontinuation rates for statin treatment regimens.
A model of statin-induced myopathy has been developed using Drosophila. Adult flies were exposed to food containing fluvastatin for 5 days prior to experimentation. Phenotypes observed include reduced locomotion activity and climbing ability, myofibrillar damage and abnormal mitochondria in skeletal muscle, impaired lipid metabolism, and impaired insulin signaling.
There is a single Drosophila ortholog of the human statin target gene HMGCR, Dmel\Hmgcr. RNAi-mediated knockdown of Hmgcr in the skeletal muscles recapitulates fluvastatin-induced mitochondrial phenotypes and results in lowered locomotion activity; however, myofibrillar damage is not observed. The role of the Drosophila skeletal muscle chloride channel, ClC-a has also been investigated.
See the FlyBase chemical report for fluvastatin (FBch0001119).
[updated Mar. 2024 by FlyBase; FBrf0222196]
Statins are considered to be safe, well tolerated and the most efficient drugs for the treatment of hypercholesterolemia, one of the main risk factor for atherosclerosis, and therefore they are frequently prescribed medications. The most severe adverse effect of statins is myotoxicity, in the form of myopathy, myalgia, myositis or rhabdomyolysis. Clinical trials commonly define statin toxicity as myalgia or muscle weakness with creatine kinase (CK) levels greater than 10 times the normal upper limit. (Tomaszewski et al., 2011; pubmed:22001973)
Despite the statin-therapy-mediated positive effects on cardiovascular events, patient compliance is often poor. Statin-associated muscle symptoms (SAMS) are the most common side effect associated with treatment discontinuation. SAMS, which range from mild-to-moderate muscle pain, weakness, or fatigue to potentially life-threatening rhabdomyolysis, are reported by 10% to 25% of patients receiving statin therapy. (Vinci et al., 2021; pubmed:34769118)
Statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR; HMG Coenzyme A reductase), are widely prescribed to lower cholesterol and low-density lipoprotein (LDL) and thus reduce cardiovascular disease mortality and morbidity (FBrf0255125 and references cited therein).
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human CLCN2 and CLCN1 (multiple homologous genes in both species).
