Skeletal muscle ceramides do not contribute to physical inactivity-induced insulin resistance

SUMMARY STATEMENT This study supports that muscle ceramide do not play a key role in insulin resistance which developed early with physical inactivity. ABSTRACT Physical inactivity increases the risk to develop type 2 diabetes, a disease characterized by a state of insulin resistance. By promoting inflammatory state, ceramides are especially recognized to alter insulin sensitivity in skeletal muscle. The present study was designed to analyze, in mice, whether muscle ceramides contribute to physical inactivity-induced insulin resistance. For this purpose, we used the wheel lock model to induce a sudden reduction of physical activity, in combination with myriocin treatment, an inhibitor of de novo ceramide synthesis. Mice were assigned to 3 experimental groups: voluntary wheel access group (Active), a wheel lock group (Inactive) and wheel lock group treated with myriocin (Inactive-Myr). We observed that 10 days of physical inactivity induces hyperinsulinemia and increase HOMA-IR. The muscle ceramide content were not modified by physical inactivity and myriocin. Thus, muscle ceramides do not play a role in physical inactivity-induced insulin resistance. In skeletal muscle, insulin-stimulated Akt phosphorylation and inflammatory pathway were not affected by physical inactivity whereas a reduction of GLUT4 content was observed. Based on these results, physical inactivity-induced insulin resistance seems related to a reduction in GLUT4 content rather than defects in insulin signaling. We observed in inactive mice that myriocin treatment improved glucose tolerance, insulin-stimulated Akt, AMPK activation and GLUT4 content in skeletal muscle. Such effects occur regardless of changes in muscle ceramide content. These findings highlight that myriocin could be a promising drug to improve glucose tolerance and insulin sensitivity.