Statin-induced myopathic changes in primary human muscle cells and reversal by a prostaglandin F2 alpha analogue

Abstract

Statin-related muscle side effects are a constant healthcare problem since patient compliance is dependent on side effects. Statins reduce plasma cholesterol levels and can prevent secondary cardiovascular diseases. Although statin-induced muscle damage has been studied, preventive or curative therapies are yet to be reported. We exposed primary human muscle cell populations (n = 22) to a lipophilic (simvastatin) and a hydrophilic (rosuvastatin) statin and analyzed their expressome. Data and pathway analyses included GOrilla, Reactome and DAVID. We measured mevalonate intracellularly and analyzed eicosanoid profiles secreted by human muscle cells. Functional assays included proliferation and differentiation quantification. More than 1800 transcripts and 900 proteins were differentially expressed after exposure to statins. Simvastatin had a stronger effect on the expressome than rosuvastatin, but both statins influenced cholesterol biosynthesis, fatty acid metabolism, eicosanoid synthesis, proliferation, and differentiation of human muscle cells. Cultured human muscle cells secreted ω-3 and ω-6 derived eicosanoids and prostaglandins. The ω-6 derived metabolites were found at higher levels secreted from simvastatin-treated primary human muscle cells. Eicosanoids rescued muscle cell differentiation. Our data suggest a new aspect on the role of skeletal muscle in cholesterol metabolism. For clinical practice, the addition of omega-n fatty acids might be suitable to prevent or treat statin-myopathy.

Zebrafish as a Model for the Study of Lipid-Lowering Drug-Induced Myopathies

“…It also disrupts their proliferation and differentiation. Furthermore, results of the study support the hypothesis that supplementation with omega-n fatty acids (eicosanoids precursors) might be beneficial as a prevention or as a treatment for patients undergoing statin therapy [ 92 ].…”

Effects of Statins on Renin–Angiotensin System

“…Simvastatin (20 mg/kg/day for 30 days) also significantly decreased prostaglandin E 2 production in rats [ 36 ] and atorvastatin (10 mg/kg) treatment of rats with periodontitis rats significantly downregulated COX-2 [ 37 ]. In another study, 96 h treatment with simvastatin reduced expression of COX-1 by suppressing fatty acid desaturase, but it increased COX-2 expression, which increased production of prostaglandins I2 and E2 [ 38 ].…”

Idiopathic Inflammatory Myopathies (IIMs)

“…This will differentiate between statin induced myopathy and relapse of immune mediated necrotizing myopathy [15]. Patients should be advised against reintroducing of statin [16].…”

“…Steroid is the corner stone although response are not equal in all subtypes, steroid sparing agent should be introduced to avoid long term complication of steroid, patient who test positive for Anti-HMGCR and anti SRP should be treated with Rituximab, patient with dermatomyositis and positive for anti-Jo1 respond will to Rituximab, as mentioned before inclusion body myositis is refractory to any treatment [16,17].…”