Modeling statin myopathy in a human skeletal muscle microphysiological system

• Published in: PloS one 2020-11, Vol.15 (11), p.e0242422
• Main Authors: Ananthakumar, Anandita, Liu, Yiling, Fernandez, Cristina E, Truskey, George A, Voora, Deepak
• Format: Article
• Language: English
• Subjects: Adverse drug reactions; Age; Aged; Amino acids; Amino Acids - pharmacology; Anticoagulants; Biology and Life Sciences; Biomedical engineering; Biopsy; Cardiovascular diseases; Cells, Cultured; Cholesterol; Complications and side effects; Correlation; Creatine; Culture Media - pharmacology; Development and progression; Documentation; Drug dosages; Exposure; Female; Fibers; Genomics; Growth media; Health risks; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hydroxymethylglutaryl-CoA Reductase Inhibitors - toxicity; Hyperlipidemia; Hyperlipidemias - drug therapy; Hyperlipidemias - pathology; Immunofluorescence; In Vitro Techniques; Kinases; Male; Medicine and Health Sciences; Middle Aged; Muscle Contraction - drug effects; Muscle Fatigue - physiology; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - physiology; Muscle, Skeletal - drug effects; Muscle, Skeletal - physiopathology; Muscles; Muscular diseases; Muscular Diseases - chemically induced; Muscular Diseases - physiopathology; Musculoskeletal system; Myoblasts; Myoblasts - drug effects; Myopathy; Patients; Precision medicine; Quadriceps Muscle - cytology; Risk factors; Side effects; Signs and symptoms; Single-Blind Method; Skeletal muscle; Statins; Tetanus; Tissue Engineering
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0242422

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