Skeletal muscle satellite cell function is largely dictated by the surrounding environment following injury. Immune cell infiltration dominates the extracellular space in the injured area, resulting in increased cytokine concentrations. While increased pro-inflammatory cytokine expression has been previously established in the first 3 days following injury, less is known about the time course of cytokine expression and the specific mechanisms of cytokine induced myoblast function. Therefore, the expression of IL-1β and IL-6 at several time points following injury, and their effects on myoblast proliferation, were examined. In order to do this, skeletal muscle was injured using barium chloride in mice and tissue was collected 1, 5, 10, and 28 days following injury. Mechanisms of cytokine induced proliferation were determined in cell culture using both primary and C2C12 myoblasts. It was found that there is a ∼20-fold increase in IL-1β (p≤0.05) and IL-6 (p = 0.06) expression 5 days following injury. IL-1β increased proliferation of both primary and C2C12 cells ∼25%. IL-1β stimulation also resulted in increased NF-κB activity, likely contributing to the increased proliferation. These data demonstrate for the first time that IL-1β alone can increase the mitogenic activity of primary skeletal muscle satellite cells and offer insight into the mechanisms dictating satellite cell function following injury.

Insulin resistance is the principle step towards the progression of type 2 diabetes, and has been linked to increased circulating levels of cytokines, leading to chronic low-grade inflammation. Specifically, in chronic disease states increased IL-6 is thought to play a critical role in the regulation of insulin resistance in the peripheral tissues, and has been used as a marker of insulin resistance. There is also an endogenous up-regulation of IL-6 in response to exercise, which has been linked to improved insulin sensitivity. This leads to the question “how can elevated IL-6 lead to the development of insulin resistance, and yet also lead to increased insulin sensitivity?” Resolving the dual role of IL-6 in regulating insulin resistance/sensitivity is critical to the development of potential therapeutic interventions. This review summarizes the literature on the seemingly paradoxical role of elevated IL-6 on insulin signalling, including the activation of AMPK and the involvement of leptin and SOCS3.

This study was designed to investigate the role of interleukin‐6 (IL‐6) on high‐fat diet (HFD)‐induced glucose intolerance, and the response to voluntary physical activity in the prevention of insulin resistance. Six‐week‐old wild‐type (WT) and IL‐6 knockout (KO) mice with (RUN) or without (SED) access to running wheels were fed a HFD (60% from kcal) for 4 weeks. A glucose tolerance test revealed that blood glucose levels were 25–30% higher in KO RUN compared to all other groups. In WT RUN, weight gain was positively correlated with total caloric intake; however, this correlation was absent in KO RUN. In soleus muscle, there was a 2‐fold increase in SOCS3 expression in KO RUN compared to all other groups. In gastrocnemius and plantaris muscles, Akt phosphorylation was 31% higher in WT RUN compared to WT SED, but this effect of running was absent in KO mice. Additionally, there was a 2.4‐fold increase in leptin expression in KO RUN compared to KO SED in the gastrocnemius and plantaris muscles. In the liver, there was a 2‐ to 3.8‐fold increase in SOCS3 expression in KO SED compared to all other groups, and AMPKα phosphorylation was 27% higher in WT mice (both RUN and SED) compared to KO mice (both RUN and SED). This study provides new insights into the role of the IL‐6 in metabolism and energy storage, and highlights tissue‐specific changes in early signaling pathways in response to HFD for 4 weeks. The collective findings suggest that endogenous IL‐6 is important for the prevention of insulin resistance leading to type 2 diabetes.