Mechanical stretch improves high glucose-induced leptin resistance thus promoting glucose uptake of C2C12 myoblasts

Exercise has been shown to alleviate central leptin resistance (LR), while the effects of exercise on peripheral especially skeletal muscle LR and its mechanisms remain poorly understood. In this study, we explored the effect and mechanisms of mechanical stretch (mimic exercise in vitro) on high glucose-induced LR of C2C12 myoblasts. We found (1) 65 mM glucose-induced LR of C2C12 cells was improved by 15 % stretch lasting for 3 or 6 h (represented as decrease of leptin and increases of leptin receptor (LepR) and glucose uptake), with more glucose uptake in 6h-stretch than 3h-stretch; (2) 15 % stretch changed the levels of important regulators of LR, including increasing signal transducer and activator of transcription 3 (STAT3), decreasing protein tyrosine phosphatase 1B (PTP1B) and suppressor of cytokine signaling-3 (SOCS3), with higher alterations of STAT3 and SOCS3 in 6h-stretch than 3h-stretch; (3) 15 % stretch activated the classical pathway regulating glucose metabolism, including increasing the levels of insulin-like growth factor (IGF-1), IGF-1 receptor (IGF-1R), insulin receptor substrate 1 (IRS-1), protein kinase B (Akt) and glucose transporter 4 (GLUT4), enhancing activities of phosphoinositide 3-kinase (PI3K) and Akt, with more increases of IGF-1R and IRS1 in 6h-stretch than 3h-stretch and enhanced GLUT4 only in 6h-stretch. Altogether, 15 % stretch alleviated high glucose-induced LR of C2C12 myoblasts through increasing STAT3 and decreasing PTP1B and SOCS3, then enhancing glucose uptake via IGF-1/IGF-1R-PI3K/Akt-GLUT4 pathway, which would deepen our understanding how exercise improved skeletal muscle LR and subsequent glucose uptake.