# Patient-specific modeling of metabolic dysfunction in statin-induced myopathy using iPSC-derived myocytes

> **NIH NIH K08** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2022 · $137,160

## Abstract

Project Summary/Abstract
Statins are the most widely used medication in reducing blood cholesterol and preventing coronary
heart disease. However, adherence is poor; studies report fewer than half of patients take statins as
prescribed. One of the main barriers in statin adherence is symptoms related to myopathy which include
muscle discomfort, weakness, and rhabdomyolysis, a potentially life-threatening condition. Yet, the underlying
mechanism of statin-induced myopathy (SIM) remains poorly understood due to 1) complex pleiotropic and
myotoxic effects of statins, 2) limited accessibility of affected patients’ myocytes, and 3) lack of appropriate
animal models to investigate the differential susceptibilities of statin toxicity. Previous clinical and scientific
findings suggest off-target effects of statins in the mitochondria as the mechanism of SIM, but the results have
not been validated in human studies.
Recent advances in the generation of skeletal muscle cells (SkMCs) from human iPSCs present an
unprecedented opportunity to model skeletal muscle diseases such as SIM. Herein, I propose to investigate
the disease mechanisms of SIM by using a patient-specific iPSC platform. Specifically, I will test the central
hypothesis that SIM is mediated via skeletal muscle-specific off-target effects resulting in mitochondrial redox
imbalance, metabolic compromise and subsequent cell death. For this study, I will first characterize metabolic
consequences of statins in iPSC-derived SkMCs and patient myocytes (Aim 1). I will then investigate the
mechanism behind patient-specific differential myopathic susceptibility to statins by comparing iPSC-SkMCs
derived from patients tolerant of statins to patients suffering from SIM (Aim 2). Finally, I will identify novel
genes critical in the pathogenesis of SIM utilizing a genome-scale CRISPR interference screening technique
by specifically silencing genes involved in statin toxicity and thereby conferring statin tolerance (Aim 3). The
findings from this study will elucidate the molecular mechanism of SIM and facilitate the creation of precision
medicine tools to enhance the diagnosis, prevention and treatment of SIM.

## Key facts

- **NIH application ID:** 10469338
- **Project number:** 5K08HL148540-04
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** June-wha Rhee
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $137,160
- **Award type:** 5
- **Project period:** 2020-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469338

## Citation

> US National Institutes of Health, RePORTER application 10469338, Patient-specific modeling of metabolic dysfunction in statin-induced myopathy using iPSC-derived myocytes (5K08HL148540-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10469338. Licensed CC0.

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