Activation of Transposable Elements in Human Skeletal Muscle Fibers upon Statin Treatment

Abstract

High cholesterol levels have been linked to a high risk of cardiovascular diseases, and preventative pharmacological care to lower cholesterol levels is critically important. Statins, which are hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are drugs used to reduce the endogenous cholesterol synthesis, thus minimizing its pathophysiological effects. Despite the proven benefits, statins therapy is known to cause a number of skeletal muscle disorders, including myalgia, myopathy and myositis. The mechanisms underlying such statin-induced side effects are unknown. Recently, a group of genes and molecular pathways has been described to participate in statin-induced myopathy, caused by either simvastatin or rosuvastatin, although the mechanism by which changes in gene regulation occur was not studied. Transposable Elements (TEs), repetitive elements that move within the genome, are known to play regulatory roles in gene expression; however, their role in statin-induced muscle damage has not been studied. We analyzed the expression of TEs in human skeletal fiber cells treated with either simvastatin or rosuvastatin, as well as their respective controls, and identified TEs that change their expression in response to the treatment. We found that simvastatin resulted in >1000 differentially expressed (DE) TEs, whereas rosuvastatin resulted in only 27 DE TEs. Using network analysis tools, we predicted the impact of the DE TEs on the expression of genes and found that amongst the genes potentially modulated by TEs, there are some previously associated to statin-linked myopathy pathways (e.g., AKT3). Overall, our results indicate that TEs may be a key player in the statin-induced muscle side effects.

Setdb1 safeguards genome integrity in muscle stem cells to allow for regenerative myogenesis and inflammation

“…Only one role for ERVs had been established in skeletal muscle, as they may be involved in statin-induced myopathies. 28,29 In contrast, our results indicate that when MuSCs exit from quiescence, ERVs de-repression has more severe consequences, triggering disaggregation of regenerating muscle fibers. We suggest that active repression of ERVs in muscle cells is a crucial process to allow for normal muscle physiology.…”

Limited stress and tissue-specific transcriptional and translational activity of transposable elements in mosquitoes

“…A recent review has revealed that several types of stress can modulate the expression of specific Drosophila TEs, with repressed TEs outnumbering induced ones among these differentially expressed elements (30). This pattern has also been observed in vertebrates, such as humans, where there are more repressed than induced TEs after exposure to some chemical compounds, such as Simvastatin (139) and short-term treatment with Morphine (140). Classical theories argue that TE induction after stress exposure acts as a force that can generate diversity, consequently contributing to the species’ adaptation to changing environments.…”

An eQTL-based Approach Reveals Candidate Regulators of LINE-1 RNA Levels in Lymphoblastoid Cells

“…Estrogens, which are involved in cholesterol and lipid metabolism, have been found to drive changes in repeat expression, and the receptors for both estrogens and androgens are believed to bind repeat DNA (Sampathkumar et al 2020; Wahl et al 2020). Pharmacological inhibition of the mitochondrial respiratory chain and pharmacological reduction of endogenous cholesterol synthesis have also been shown to induce changes in L1 protein levels or repeat expression more broadly (Baeken et al 2020; Valdebenito-Maturana et al 2023). GSEA with the GO Biological Process gene sets ( Figure 3F , Supplementary Table S4X ) and the Reactome gene sets ( Figure 3F , Supplementary Table S3Y ) also identified several metabolism-related pathways including “ATP metabolic process”, “Generation of precursor metabolites and energy”, and “metabolism of amino acids and derivatives”.…”