Abstract 10390: Simvastatin Increases Irisin Concentrations in Human Subjects in Vivo and Irisin Expression and Secretion in Human Skeletal Muscle Cells ex Vivo
Introduction: Irisin is a muscle-tissue-secreted peptide, a myokine, is induced by exercise and can convert white fat into brown fat. Little is known about the association of irisin with metabolic parameters and especially with parameters involved in lipid metabolism.
Hypothesis: We assessed the hypothesis that lipid-lowering drugs such as simvastatin and ezetimibe influence serum irisin concentrations.
Methods: A prospective, randomized, parallel 3-group study was performed in 72 healthy men (mean age 32±9 years, mean BMI 25.7±3.2 kg/m2). Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination. The effects of simvastatin were also investigated in primary human skeletal muscle cells (HSKMCs).
Results: Baseline irisin concentrations (mean ± SD, 265 ± 102 ng/ml, range 85 to 518 ng/ml) were not significantly correlated with age, BMI, eGFR, thyroid parameters, glucose, insulin, lipoproteins, non-cholesterol sterols (campesterol, latosterol), adipokines (resistin, adiponectin, leptin), inflammation markers (interleukin-6, hsCRP, LP-PLA2) and various molecular markers of cholesterol metabolism. Circulating irisin increased significantly in simvastatin-treated (+13.8±28.9%, P=0.01) but not in ezetimibe-treated subjects (P=0.1). 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 its precursor fibronectin type III domain containing 5 (FNDC5) mRNA expression (p<0.05). The upstream regulator of FNDC5, PPARγ co-activator-1α (PGC-1α), was also increased in response to treatment with simvastatin (p<0.05), as were unspecific markers of cellular stress, such as atrogin-1 and Bcl-2/Bax gene and protein expression, respectively (p<0.05).
Conclusions: Simvastatin increases irisin concentrations in vivo and in vitro. It remains to be determined whether this increase is due to a direct stimulation of its upstream regulator, PGC-1α, and its precursor FNDC5 or whether muscle cell oxidative stress and apoptosis are associated with elevated irisin.
- © 2013 by American Heart Association, Inc.