Positive association between musclin and insulin resistance in obesity: evidence of a human study and an animal experiment

Background: Musclin is a novel skeletal muscle-derived secretory factor considered to be a potent regulator of the glucose metabolism and therefore may contribute to the pathogenesis of obesity and insulin resistance (IR). Methods: To test this hypothesis, we examined the plasma musclin levels in overweight/obese subjects and lean controls. Rats on a high fat diet (HFD) were used as the annimal model of obesity. Radioimmunoassay and western blot were used to determine musclin levels in plasma and skeletal muscle. Results: According to radioimmunoassays, the overweight/obese subjects exhibited elevated musclin plasma levels compared with the lean controls (89.49 +/- 19.00 ng/L vs 80.39 +/- 16.35 ng/L, P < 0.01). The musclin levels were positively correlated with triglyceride, fasting plasma glucose, and homeostasis model assessment of IR levels. These observations were confirmed with a high-fat diet(HFD) rat model. HFD rats also exhibited increased musclin immunoreactivity in plasma (P < 0.01) and in skeletal muscle (P < 0.05), as well as increased musclin mRNA levels in skeletal muscle (P < 0.01). Musclin incubation significantly inhibited muscles H-3-2-DG uptake in the normal diet(ND) group (P < 0.01). The protein expression of glucose transporter type 4 was significantly down regulated by 30% (P < 0.05) in the ND group after soleusmuscle was incubated with musclin compared with the control. Musclin incubation also increased the protein levels of glucose-regulated protein (GRP) 78 and GRP94 by 146.8 and 54% (both P < 0.05), respectively, in ND rats. Conclusions: Our data support the hypothesis that musclin has a strong relationship with obesity-associated IR by impairing the glucose metabolism and, at least in part, through causing endoplasmic reticulum stress.