Modeling statin myopathy in a human skeletal muscle microphysiological system.

Anandita Ananthakumar,Yiling Liu,George A Truskey,Deepak Voora,Cristina E Fernandez

doi:10.1371/journal.pone.0242422

Abstract

Statins are used to lower cholesterol and prevent cardiovascular disease. Musculoskeletal side effects known as statin associated musculoskeletal symptoms (SAMS), are reported in up to 10% of statin users, necessitating statin therapy interruption and increasing cardiovascular disease risk. We tested the hypothesis that, when exposed to statins ex vivo, engineered human skeletal myobundles derived from individuals with (n = 10) or without (n = 14) SAMS and elevated creatine-kinase levels exhibit statin-dependent muscle defects. Myoblasts were derived from muscle biopsies of individuals (median age range of 62–64) with hyperlipidemia with (n = 10) or without (n = 14) SAMS. Myobundles formed from myoblasts were cultured with growth media for 4 days, low amino acid differentiation media for 4 days, then dosed with 0 and 5μM of statins for 5 days. Tetanus forces were subsequently measured. To model the change of tetanus forces among clinical covariates, a mixed effect model with fixed effects being donor type, statin concentration, statin type and their two way interactions (donor type*statin concentration and donor type* statin type) and the random effect being subject ID was applied. The results indicate that statin exposure significantly contributed to decrease in force (P<0.001) and the variability in data (R2C [R square conditional] = 0.62). We found no significant differences in force between myobundles from patients with/without SAMS, many of whom had chronic diseases. Immunofluorescence quantification revealed a positive correlation between the number of straited muscle fibers and tetanus force (R2 = 0.81,P = 0.015) and negative correlation between number of fragmented muscle fibers and tetanus force (R2 = 0.482,P = 0.051) with no differences between donors with or without SAMS. There is also a correlation between statin exposure and presence of striated fibers (R2 = 0.833, P = 0.047). In patient-derived myobundles, statin exposure results in myotoxicity disrupting SAA organization and reducing force. We were unable to identify differences in ex vivo statin myotoxicity in this system. The results suggest that it is unlikely that there is inherent susceptibility to or persistent effects of statin myopathy using patient-derived myobundles.

Highlights

Statins are selective 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and are among the most commonly used medications to lower cholesterol and prevent cardiovascular diseases [1]
Myalgias typically refer to symptoms without associated elevations in serum creatine kinase (CK) during statin use and are reported to occur at frequencies ranging from 1% to 10% [3]
The patients were recruited from the same clinics and had expected chronic conditions for patients with statin myopathy

Summary

Introduction

Statins are selective 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and are among the most commonly used medications to lower cholesterol and prevent cardiovascular diseases [1]. Randomized controlled trials demonstrate that statins are safe to use, statin associated musculoskeletal symptoms (SAMS) in the form of myopathy, myalgia, myositis, or rhabdomyolysis have been reported [2]. Myalgias typically refer to symptoms (pain, tenderness, or weakness) without associated elevations in serum creatine kinase (CK) during statin use and are reported to occur at frequencies ranging from 1% to 10% [3]. Myopathy typically refers to myalgias associated with elevation in serum CK level and occurs at a lower frequency (

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