# A novel gene and mechanisms for statin-induced myopathy in the mouse

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $205,920

## Abstract

SUMMARY/ABSTRACT
Cholesterol-lowering statin drugs significantly reduce cardiovascular morbidity and mortality, but a subset of
statin users experience muscle pain/weakness, which limits the utility of statins in these individuals. A better
understanding of the genetic predisposition to statin-induced myopathy will advance our understanding of the
pathogenesis and also suggest new strategies to prevent and treat these symptoms. This application builds on
our identification of a novel genetic locus that influences susceptibility to statin-induced myopathy. Using a
unique genetic reference panel of 94 diverse inbred mouse strains, we assessed the adverse effects of
simvastatin in more than 800 individual mice. Our integrated analysis of genome-wide association (GWAS) and
expression quantitative loci (eQTL) data identified Tpmt as a high-probability casual gene that is specifically
associated with statin-induced myopathy. The Tpmt gene encodes the enzyme thiopurine S-methyltransferase
(TPMT), which metabolizes xenobiotics such as thiopurine drugs; the only known endogenous substrate is
selenocysteine, an amino acid that is selectively incorporated into selenoproteins, which have critical roles in
maintaining cellular redox state. Selenoprotein synthesis requires isopentenyl intermediates that are produced
by the HMG CoA pathway for cholesterol synthesis, and which are reduced in the presence of statins.
Interestingly, insufficiency of some selenoproteins causes muscle symptoms that resemble statin-induced
myopathy. We hypothesize that genetic variation in Tpmt expression levels in combination with statin
treatment constitutes a two-hit mechanism for the induction of statin myopathy: (1) statin limits the supply
of isopentenyl groups for selenocysteine synthesis, and (2) genetic variation causing elevated TPMT levels
reduces the pool of selenocysteine available for protein synthesis. We will test our hypothesis using a
combination of in vivo and in vitro studies. In Aim 1, we will determine the effect of modulating Tpmt levels in
statin-treated mice through gain- and loss-of-function approaches using adeno-associated virus (AAV)-mediated
gene transfer into genetic backgrounds that we have defined as myopathy-susceptible or -resistant. Conversion
between myopathy sensitivity and resistance will provide strong evidence that Tpmt is a statin myopathy
susceptibility gene. In Aim 2, we will investigate each component of the statin–TPMT–selenoprotein axis for
potential contributions to statin myopathy. We will first assess whether modulation of Tpmt expression levels
alters selenoprotein levels in vivo and in cultured hepatocytes. We will next determine whether selenoprotein
levels influence statin-induced myotoxicity in cultured myotubes. Finally, we will assess the effects of
statin/selenoproteins on myocyte mitochondrial function and reactive oxygen species levels. The completion of
our aims will contribute insights into the genetic susceptibility and p...

## Key facts

- **NIH application ID:** 10041615
- **Project number:** 1R21AR077782-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Karen Reue
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $205,920
- **Award type:** 1
- **Project period:** 2020-09-17 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10041615

## Citation

> US National Institutes of Health, RePORTER application 10041615, A novel gene and mechanisms for statin-induced myopathy in the mouse (1R21AR077782-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10041615. Licensed CC0.

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