Translational insights into statin-induced myotoxicity: Differential impact of lipophilic and hydrophilic statins on iPSC-derived skeletal muscle cells from patients with familial hypercholesterolemia

Abstract

Statins are highly effective cholesterol-lowering drugs that can reduce the risk of cardiovascular events. Statins are well tolerated but some patients experience statin-associated muscle symptoms (SAM) that can reduce adherence to therapy. We investigated molecular mechanisms statin-induced myotoxicity using induced pluripotent stem cells (iPSC)-derived skeletal muscle (SKgM) cells. iPSC-SKgM cells were obtained from patients with familial hypercholesterolemia (FH) experiencing SAM (n = 3) or not (nonSAM, n = 3). iPSC-SkgM cells were treated with atorvastatin and rosuvastatin (1 to 100 µM). Statin cytotoxicity was assessed by functional assays (cell death, mitochondrial damage, caspase 3/7 activity). iPSC-SkgM cells from SAM patients were more sensitive to atorvastatin toxicity than nonSAM cells (p < 0.05), recapitulating the phenotype of SAM patients. Rosuvastatin was less cytotoxic than atorvastatin in iPSC-SkgM (p < 0.05) from both SAM and nonSAM patients. Transcriptomic analysis revealed stronger effects on gene expression in SAM-derived iPSC-SKgM cells treated with atorvastatin (106 genes) than rosuvastatin (33 genes) compared to nonSAM cells. Enrichment analyses predicted associations of these genes with cell growth, muscle function, pro-inflammatory processes, and apoptosis. Proteomic analysis also showed more proteins differentially abundant in atorvastatin (61 proteins) than in rosuvastatin (26 proteins) treated cells. These proteins were related to cell biosynthetic process, signaling and communication, nucleic acid metabolism, and protein processing. In conclusion, atorvastatin has greater toxicity than rosuvastatin to iPSC-SKgM cells, an outcome exacerbated in FH patients who experienced SAM. Atorvastatin has stronger effects on expression of molecules involved in several signaling pathways suggesting novel molecular mechanisms of statin-induced myotoxicity.

Keywords: IPSC; Proteomics; Skeletal muscle cells; Statin myotoxicity; Transcriptomics.