Undercarboxylated osteocalcin (ucOC) improves insulin sensitivity in mice. Previously we found that ucOC augmented insulin-stimulated glucose uptake in mice EDL muscles after ex vivo contraction. However, whether ucOC also directly enhances basal muscle glucose uptake and whether these effects are muscle-type specific are still not clear. We hypothesised that ucOC will increase glucose uptake in both EDL and soleus muscles, with or without the presence of insulin, via the activation of ERK.

EDL and soleus muscles from male C57BL/6 mice were isolated and split longitudinally. Samples were pretreated with the ERK inhibitor U0126 or DMSO vehicle, followed by 90 minutes treatment of ucOC or KHB buffer control. Insulin or control was added in the last 30 minutes. After the treatment, muscle glucose uptake and signaling proteins were assessed.

ucOC significantly increased basal, non-insulin, stimulated EDL (45.4%, p<0.001) and soleus (31.2%, p<0.01) glucose uptake and basal phosphorylation of ERK2, mTOR, AKT, and AS160. Treatment with U0126 reduced the ucOC-induced increase in muscle glucose uptake in both muscles (Cohen’s d>0.2). The inhibitor also completely blocked the ucOC effects on the phosphorylation of AKT and AS160 in EDL (Cohen’s d>0.8), and attenuated these ucOC effects in soleus (Cohen’s d>0.2). ucOC significantly augmented insulin-stimulated glucose uptake (28.8%, p<0.05) and potentiated insulin-stimulated phosphorylation of ERK2, mTOR, AKT, and AS160 only in soleus. However, the ERK inhibitor had little impact on the ucOC effects on insulin-stimulated phosphorylation of AKT and AS160 (Cohen’s d<0.2).

Taken together, we, for the first time, showed that ucOC can increase basal glucose uptake in both glycolytic and oxidative muscles in mice, and has insulin-sensitising effect on oxidative muscle only. We also demonstrated that ucOC exerts the beneficial effects on basal muscle glucose uptake and mTOR-AKT-AS160 axis, at least in part, via ERK activation.