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Modeling statin myopathy in a human skeletal muscle microphysiological system
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 teste...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688150/ https://www.ncbi.nlm.nih.gov/pubmed/33237943 http://dx.doi.org/10.1371/journal.pone.0242422 |
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author | Ananthakumar, Anandita Liu, Yiling Fernandez, Cristina E. Truskey, George A. Voora, Deepak |
author_facet | Ananthakumar, Anandita Liu, Yiling Fernandez, Cristina E. Truskey, George A. Voora, Deepak |
author_sort | Ananthakumar, Anandita |
collection | PubMed |
description | 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 (R(2)C [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 (R(2) = 0.81,P = 0.015) and negative correlation between number of fragmented muscle fibers and tetanus force (R(2) = 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 (R(2) = 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. |
format | Online Article Text |
id | pubmed-7688150 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-76881502020-12-05 Modeling statin myopathy in a human skeletal muscle microphysiological system Ananthakumar, Anandita Liu, Yiling Fernandez, Cristina E. Truskey, George A. Voora, Deepak PLoS One Research Article 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 (R(2)C [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 (R(2) = 0.81,P = 0.015) and negative correlation between number of fragmented muscle fibers and tetanus force (R(2) = 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 (R(2) = 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. Public Library of Science 2020-11-25 /pmc/articles/PMC7688150/ /pubmed/33237943 http://dx.doi.org/10.1371/journal.pone.0242422 Text en © 2020 Ananthakumar et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Ananthakumar, Anandita Liu, Yiling Fernandez, Cristina E. Truskey, George A. Voora, Deepak Modeling statin myopathy in a human skeletal muscle microphysiological system |
title | Modeling statin myopathy in a human skeletal muscle microphysiological system |
title_full | Modeling statin myopathy in a human skeletal muscle microphysiological system |
title_fullStr | Modeling statin myopathy in a human skeletal muscle microphysiological system |
title_full_unstemmed | Modeling statin myopathy in a human skeletal muscle microphysiological system |
title_short | Modeling statin myopathy in a human skeletal muscle microphysiological system |
title_sort | modeling statin myopathy in a human skeletal muscle microphysiological system |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688150/ https://www.ncbi.nlm.nih.gov/pubmed/33237943 http://dx.doi.org/10.1371/journal.pone.0242422 |
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