Ex vivo metabolomic profiling of statin-induced myopathy
Description: 'Statins' are widely used to reduce cardiovascular morbidity and mortality with over 56 million Americans currently eligible for statin therapy. While safe and well tolerated, a significant proportion (1 in 20) of patients will develop statin-associated musculoskeletal symptoms (SAMS) that either limit or interfere with the effective statin therapy. Therefore, millions are denied the cardiovascular benefits of these life saving medications due to concerns over SAMS. Alternative PCSK9 inhibitors are now options for patients with SAMS; however their cost, limited track record, and lack of biomarkers to diagnose SAMS make statins the preferred agents for cost-effective cardiovascular risk reduction. There are unmet needs for deeper mechanistic insights into SAMS and novel biomarkers for its diagnosis and monitoring. This proposal leverages two highly innovative tools to study SAMS. The first is an ex vivo system where patient-derived skeletal muscle myoblasts are used to engineer a three-dimensional 'myobundle' that can be exposed to statins ex vivo and studied for physiologic and molecular changes. The second employs the science of metabolomics to study the biochemistry underlying drug toxicity. We are currently collecting and banking myobundles from patients with vs. without a history of severe, SAMS and exposing them to escalating concentrations of statins ex vivo in conjunction with physiologic and histologic measurements. This proposal will complement these data by adding molecular data and pursuing two Aims: Aim 1 ' Identify metabolic changes associated with ex vivo statin-induced myotoxicity. We hypothesize that metabolites (acylcarnitines, amino acids, hexoses, phospho- and sphingolipids and/or biogenic amines) are associated with statin-induced reductions in ex vivo force generation (1a) and mitochondrial function (1b). Aim 2 ' Identify metabolic changes associated with clinical statin induced myopathy. We hypothesize that metabolites are associated with SAMS at baseline or in response to statin exposure compared to patients who are tolerating statin therapy. The expected outcome will be a preliminary biochemical understanding of SAMS in patient-derived skeletal muscle and the foundation for novel biomarkers. Future steps include deeper biochemical studies, manipulation of myobundles to test novel mechanisms for SAMS, and novel therapies to prevent/mitigate SAMS.
Funder: American Heart Association
Amount: $149,000
Funding type: research
Funder scheme: Innovative Research Grant
Start date: 2017-01-01
End date: 2018-12-31
Investigators: Deepak Voora, Deepak Voora
Institution: Duke University School of Medicine
Funded outputs count: 0
Funder award ID: 17IRG33410539
OpenAlex ID: G8255559831