Effects of Lipid-Lowering Drugs on Irisin in Human Subjects In Vivo and in Human Skeletal Muscle Cells Ex Vivo

Abstract

Context and ObjectiveThe myokine irisin has been proposed to regulate energy homeostasis. Little is known about its association with metabolic parameters and especially with parameters influencing pathways of lipid metabolism. In the context of a clinical trial, an exploratory post hoc analysis has been performed in healthy subjects to determine whether simvastatin and/or ezetimibe influence serum irisin levels. The direct effects of simvastatin on irisin were also examined in primary human skeletal muscle cells (HSKMCs).Design and ParticipantsA randomized, parallel 3-group study was performed in 72 men with mild hypercholesterolemia and without apparent cardiovascular disease. Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination.ResultsBaseline irisin concentrations were not significantly correlated with age, BMI, estimated GFR, thyroid parameters, glucose, insulin, lipoproteins, non-cholesterol sterols, adipokines, inflammation markers and various molecular markers of cholesterol metabolism. Circulating irisin increased significantly in simvastatin-treated but not in ezetimibe-treated subjects. The changes were independent of changes in LDL-cholesterol and were not correlated with changes in creatine kinase levels. In HSKMCs, simvastatin significantly increased irisin secretion as well as mRNA expression of its parent peptide hormone FNDC5. Simvastatin significantly induced cellular reactive oxygen species levels along with expression of pro- and anti-oxidative genes such as Nox2, and MnSOD and catalase, respectively. Markers of cellular stress such as atrogin-1 mRNA and Bax protein expression were also induced by simvastatin. Decreased cell viability and increased irisin secretion by simvastatin was reversed by antioxidant mito-TEMPO, implying in part that irisin is secreted as a result of increased mitochondrial oxidative stress and subsequent myocyte damage.ConclusionsSimvastatin increases irisin concentrations in vivo and in vitro. It remains to be determined whether this increase is a result of muscle damage or a protective mechanism against simvastatin-induced cellular stress.Trial RegistrationClinicalTrials.gov NCT00317993 NCT00317993.

Circulating levels of irisin is elevated in hypothyroidism, a case-control study

“…Gouni-Berthold and cols. also examined the relationship between irisin levels and TFT on 72 male patients, who used lipid-lowering medicine, and found no statistically significant relationship either in the groups or in the whole population (19). The results of their study are in consistence with our results since their study was performed with patients without euthyroid or another documented thyroid disease.…”

New insights into the effects of irisin levels in HIV-infected subjects: correlation with adiposity, fat-free mass, and strength parameters

“…Recent data has revealed that lipid-lowering drugs affect circulating irisin levels in humans and PIs increase HDL cholesterol levels in women infected with HIV (26). In this sense, women presented longer infection and HAART durations when compared with men, although this finding was not significant, while a poor correlation between HAART and irisin levels was observed.…”

Irisin is a biomarker for metabolic syndrome in prepubertal children

“…In our study, irisin concentrations were more likely to be lower in overweight and obese children compared to normal-weight children, and irisin exhibited a significant inverse correlation with BMI SDS in all the children in this study. Studies have reported that irisin is related to BMI; however, irisin was not significantly correlated with BMI in other studies [23,24]. The circulating irisin levels have been shown to be negatively correlated with BMI [25][26][27], whereas some reports suggested that irisin concentrations were positively associated with BMI [20,28].…”