Centre of Inflammation and Metabolism, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Am J Physiol Endocrinol Metab. 2012 Jul 15;303(2):E283-92. doi: 10.1152/ajpendo.00586.2011. Epub 2012 May 29.
The cytokine leukemia-inhibitory factor (LIF) is expressed by skeletal muscle and induces proliferation of muscle precursor cells, an important feature of skeletal muscle maintenance and repair. We hypothesized that muscle precursor cells from patients with type 2 diabetes had a deficient response to LIF. The mRNA and protein expressions of LIF and its receptor (LIFR) were measured in skeletal muscle biopsies from healthy individuals and patients with type 2 diabetes by use of qPCR and Western blot. LIF signaling and response were studied following administration of recombinant LIF and siRNA knockdown of suppressor of cytokine signaling (SOCS)3 in myoblast cultures established from healthy individuals and patients with type 2 diabetes. Myoblast proliferation rate was assessed by bromodeoxyuridine incorporation. LIF and LIFR proteins were increased in both muscle tissue and cultured myoblasts from diabetic patients. Nonetheless, in the diabetic myoblasts, LIF-induced phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3 was impaired. The deficient response to LIF administration in the diabetic myoblasts was further emphasized by a lack of increase in LIF-stimulated cell proliferation and a decreased LIF-stimulated induction of the proliferation-promoting factors cyclin D1, JunB, and c-myc. SOCS3 protein was upregulated in diabetic myoblasts, and knockdown of SOCS3 rescued LIF-induced gene expression in diabetic myoblasts, whereas neither STAT1 or STAT3 signaling nor proliferation rate was affected. In conclusion, although LIF and LIFR proteins were increased in muscle tissue and myoblasts from diabetic patients, LIF signaling and LIF-stimulated cell proliferation were impaired in diabetic myoblasts, suggesting a novel mechanism by which muscle function is compromised in diabetes.
细胞因子白血病抑制因子（LIF）由骨骼肌表达，并诱导肌肉前体细胞增殖，这是维持和修复骨骼肌的重要特征。我们假设 2 型糖尿病患者的肌肉前体细胞对 LIF 的反应不足。通过 qPCR 和 Western blot 测量了来自健康个体和 2 型糖尿病患者的骨骼肌活检中的 LIF 和其受体（LIFR）的 mRNA 和蛋白表达。在从健康个体和 2 型糖尿病患者建立的成肌细胞培养物中，用重组 LIF 给药和抑制细胞因子信号转导（SOCS）3 的 siRNA 敲低研究了 LIF 信号转导和反应。通过溴脱氧尿苷掺入评估成肌细胞增殖率。LIF 和 LIFR 蛋白在糖尿病患者的肌肉组织和培养的成肌细胞中均增加。尽管如此，在糖尿病成肌细胞中，LIF 诱导的信号转导子和转录激活子（STAT）1 和 STAT3 的磷酸化受损。在糖尿病成肌细胞中，缺乏对 LIF 给药的反应进一步强调了 LIF 刺激细胞增殖没有增加，并且 LIF 刺激的增殖促进因子 cyclin D1、JunB 和 c-myc 的诱导减少。SOCS3 蛋白在糖尿病成肌细胞中上调，并且 SOCS3 的敲低挽救了糖尿病成肌细胞中 LIF 诱导的基因表达，而 STAT1 或 STAT3 信号转导或增殖率不受影响。总之，尽管 LIF 和 LIFR 蛋白在糖尿病患者的肌肉组织和成肌细胞中增加，但 LIF 信号转导和 LIF 刺激的细胞增殖在糖尿病成肌细胞中受损，这表明了一种新的机制，即肌肉功能在糖尿病中受损。
