TY - JOUR
T1 - Statin-induced myopathic changes in primary human muscle cells and reversal by a prostaglandin F2 alpha analogue
AU - Grunwald, Stefanie Anke
AU - Popp, Oliver
AU - Haafke, Stefanie
AU - Jedraszczak, Nicole
AU - Grieben, Ulrike
AU - Saar, Kathrin
AU - Patone, Giannino
AU - Kress, Wolfram
AU - Steinhagen-Thiessen, Elisabeth
AU - Dittmar, Gunnar
AU - Spuler, Simone
N1 - Funding Information:
We thank all patients for participating in the study. We thank Friedrich C. Luft for discussing the manuscript field we particularly thank Wolf-Hagen Schunand Susanne Wissler for help with Endnote®ck. This work was funded by the German Research Society (DFG) . For his expertise in eicosanoid and beneficial discussions in this
Funding Information:
KFO192/2. Open Access publication was supported by the Publication Fund of the German Research Foundation (DFG) and the Charité Universitätsmedizin Berlin.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Statin-related muscle side effects are a constant healthcare problem since patient compliance is dependent on side effects. Statins reduce plasma cholesterol levels and can prevent secondary cardiovascular diseases. Although statin-induced muscle damage has been studied, preventive or curative therapies are yet to be reported. We exposed primary human muscle cell populations (n = 22) to a lipophilic (simvastatin) and a hydrophilic (rosuvastatin) statin and analyzed their expressome. Data and pathway analyses included GOrilla, Reactome and DAVID. We measured mevalonate intracellularly and analyzed eicosanoid profiles secreted by human muscle cells. Functional assays included proliferation and differentiation quantification. More than 1800 transcripts and 900 proteins were differentially expressed after exposure to statins. Simvastatin had a stronger effect on the expressome than rosuvastatin, but both statins influenced cholesterol biosynthesis, fatty acid metabolism, eicosanoid synthesis, proliferation, and differentiation of human muscle cells. Cultured human muscle cells secreted ω-3 and ω-6 derived eicosanoids and prostaglandins. The ω-6 derived metabolites were found at higher levels secreted from simvastatin-treated primary human muscle cells. Eicosanoids rescued muscle cell differentiation. Our data suggest a new aspect on the role of skeletal muscle in cholesterol metabolism. For clinical practice, the addition of omega-n fatty acids might be suitable to prevent or treat statin-myopathy.
AB - Statin-related muscle side effects are a constant healthcare problem since patient compliance is dependent on side effects. Statins reduce plasma cholesterol levels and can prevent secondary cardiovascular diseases. Although statin-induced muscle damage has been studied, preventive or curative therapies are yet to be reported. We exposed primary human muscle cell populations (n = 22) to a lipophilic (simvastatin) and a hydrophilic (rosuvastatin) statin and analyzed their expressome. Data and pathway analyses included GOrilla, Reactome and DAVID. We measured mevalonate intracellularly and analyzed eicosanoid profiles secreted by human muscle cells. Functional assays included proliferation and differentiation quantification. More than 1800 transcripts and 900 proteins were differentially expressed after exposure to statins. Simvastatin had a stronger effect on the expressome than rosuvastatin, but both statins influenced cholesterol biosynthesis, fatty acid metabolism, eicosanoid synthesis, proliferation, and differentiation of human muscle cells. Cultured human muscle cells secreted ω-3 and ω-6 derived eicosanoids and prostaglandins. The ω-6 derived metabolites were found at higher levels secreted from simvastatin-treated primary human muscle cells. Eicosanoids rescued muscle cell differentiation. Our data suggest a new aspect on the role of skeletal muscle in cholesterol metabolism. For clinical practice, the addition of omega-n fatty acids might be suitable to prevent or treat statin-myopathy.
UR - http://www.scopus.com/inward/record.url?scp=85079083835&partnerID=8YFLogxK
U2 - 10.1038/s41598-020-58668-2
DO - 10.1038/s41598-020-58668-2
M3 - Article
C2 - 32034223
AN - SCOPUS:85079083835
SN - 2045-2322
VL - 10
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 2158
ER -