University of Cologne, Center for Endocrinology, Diabetes and Preventive Medicine, Cologne, Germany.
PLoS One. 2013 Sep 2;8(9):e72858. doi: 10.1371/journal.pone.0072858. eCollection 2013.
The 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).
A 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.
Baseline 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.
Simvastatin 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.
ClinicalTrials.gov NCT00317993 NCT00317993.
肌因子鸢尾素被认为可以调节能量稳态。然而，人们对其与代谢参数的关系，特别是与脂质代谢途径相关参数的关系知之甚少。在一项临床试验的背景下，对健康受试者进行了一项探索性事后分析，以确定辛伐他汀和/或依折麦布是否会影响血清鸢尾素水平。此外，还在原代人骨骼肌细胞（HSKMCs）中检查了辛伐他汀对鸢尾素的直接作用。
对 72 名患有轻度高胆固醇血症且无明显心血管疾病的男性进行了一项随机、平行的 3 组研究。每组 24 名受试者分别接受为期 14 天的辛伐他汀 40mg、依折麦布 10mg 或两者联合治疗。
基线鸢尾素浓度与年龄、BMI、估算肾小球滤过率、甲状腺参数、血糖、胰岛素、脂蛋白、非胆固醇甾醇、脂肪因子、炎症标志物以及胆固醇代谢的各种分子标志物均无显著相关性。在接受辛伐他汀治疗的受试者中，循环鸢尾素水平显著升高，但在接受依折麦布治疗的受试者中则没有。这些变化与 LDL-胆固醇的变化无关，也与肌酸激酶水平的变化无关。在 HSKMCs 中，辛伐他汀显著增加了鸢尾素的分泌，以及其母肽激素 FNDC5 的 mRNA 表达。辛伐他汀还显著诱导了细胞活性氧水平，同时表达了 Nox2、MnSOD 和过氧化氢酶等促氧化和抗氧化基因。辛伐他汀还诱导了细胞应激标志物如atrogin-1mRNA 和 Bax 蛋白的表达。抗氧化剂 mito-TEMPO 逆转了辛伐他汀引起的细胞活力降低和鸢尾素分泌增加，这表明部分原因是鸢尾素是作为增加的线粒体氧化应激和随后的肌细胞损伤的结果而分泌的。
辛伐他汀在体内和体外均增加鸢尾素浓度。目前尚不清楚这种增加是肌肉损伤的结果，还是对辛伐他汀诱导的细胞应激的一种保护机制。
ClinicalTrials.gov NCT00317993 NCT00317993。
