Regulation of Myogenesis and Myocyte Glucose Uptake by Interleukin-4

Objectives: The anti-inflammatory cytokine interleukin-4 promotes glucose tolerance and insulin sensitivity, which suggests the participation of interleukin-4 in insulin signaling and metabolic homeostasis. The effects of interleukin-4 on energy metabolism in muscle, the largest insulin-targeting organ, remain obscure. Therefore, the present study aimed at investigating the roles of interleukin-4 in energy metabolism of muscle cells.

Methods: Effects of interleukin-4 on myogenesis were examined. In addition, the interaction between interleukin-4 and insulin in mediating glucose metabolism of C2C12 myoblasts and the terminal differentiated C2C12 myocytes were analyzed. Regulation of interleukin-4 to Akt and glycogen synthase kinase-3β in muscle under diabetic or insulin-resistant condition was also examined in vivo.

Results: Interleukin-4 promoted myogenesis by upregulating the expression of myocyte-specific markers, including muscle-restricted coiled-coil protein, myogenin, and myosin heavy chain. Interleukin-4 enhanced glucose uptake by boosting insulin signaling. In diabetic mice with insulin resistance, transient and long-term interleukin-4 showed differential effects on insulin signaling molecules and efficacy. Long-term interleukin-4 was insufficient to ameliorate insulin resistance probably due to physical adaptation under consistent interleukin-4 exposure for meeting the in vivo energy demands to maintain homeostasis.

Conclusions: In addition to promoting myogenesis, interleukin-4 modulates energy metabolism through multiple functions. Interleukin-4 improves glucose uptake of muscle cells under physiological condition. Nevertheless, insulin resistance takes the dominant role to determine cellular responses to external stimuli once it is developed. This study provides evidence to address the roles of cytokine in glucose metabolism as well as the interaction between immune responses and energy homeostasis.