Abstract
Previous studies have reported profound changes in metabolic fuel utilization pathways during the development of heart failure, including changes in glucose uptake, glucose transporter mislocalization and/or Insulin-resistance. insulin stimulates glucose transport in muscle cells by triggering redistribution of the GLUT4 glucose transporter from an intracellular perinuclear location to the cell surface. Multiple reports have shown that the microtubules in adipocytes and muscle cells play an important role in the insulin-stimulated glucose transport process. We recently demonstrated, using a tunable stiffness substrate mimicking disease myocardium, that we could induces early, cell-autonomous remodeling of adult cardiomyocytes that is dependent on detyrosination of α-tubulin. We therefore employed this culture substrate to define how adult isolated rat cardiomyocytes glucose uptake response is to Insulin when cultured on stiff vs. soft. At the same time, we studied the localization and expression of Glut4 transporter. We found that 48h on stiff substrate was sufficient to induce a loss of insulin sensitivity in our isolated cardiomyocytes. Immunofluorescence reveals a decrease of Glut4 at the Intercalated disc (ID) but show increase of aggregates of the Glut4 transporter at the cell surface. Western Blot analyses shows no change in the total expression of the transporter. Finally, knowing the importance of microtubules network in the trafficking of Glut4, we overexpressed of tubulin tyrosine ligase (TTL) to prevent the detyrosination of microtubules. Surprisingly, TTL not only restored Glut4 at the ID and decreased the number of aggregates, but it also significantly increased glucose uptake as well as the total amount of Glut4 by more than 2-fold compared to soft control. In conclusion, we demonstrated the importance of microtubule dynamics in cardiomyocytes for the Insulin-dependent trafficking of Glut4 to the membrane.
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