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.
Highlights
Irisin is a newly identified hormone secreted by myocytes that has been proposed to mediate beneficial effects of exercise and to influence multiple metabolic pathways, such as energy and glucose metabolism [1,2,3]
Markers of cellular stress such as atrogin-1 mRNA and Bax protein expression were 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
Summary
Irisin is a newly identified hormone secreted by myocytes (i.e., a myokine) that has been proposed to mediate beneficial effects of exercise and to influence multiple metabolic pathways, such as energy and glucose metabolism [1,2,3]. Statins are widely used in the treatment of hypercholesterolemia and for reducing cardiovascular risk [8]. This becomes of particular interest given recent data indicating that statin treatment and increased cardiovascular fitness, which would be expected to elevate irisin levels, are both associated with low mortality among dyslipidemic individuals [9]. The combination of statin treatment and increased fitness resulted in substantially lower mortality risk than either alone, reinforcing the importance of physical activity for individuals with dyslipidemia. Similar to physical activity, statins may increase irisin levels and affect metabolism and improve risk among dyslipidemic individuals through the irisin pathway too remains to be explored
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