The phosphodiesterase 5 inhibitor tadalafil regulates lipidic homeostasis in human skeletal muscle cell metabolism
| Autor: | Francesco Marampon, Erica Sarchielli, Silvia Migliaccio, Andrea Lenzi, Cristina Antinozzi, Gabriella B. Vannelli, Clarissa Corinaldesi, Clara Crescioli, L. Di Luigi |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
insulin medicine.medical_specialty medicine.drug_mechanism_of_action Endocrinology Diabetes and Metabolism Caveolin 1 PDE5i PDE5i Tadalafil Insulin Skeletal muscle Metabolism 03 medical and health sciences Endocrinology Internal medicine medicine Homeostasis Humans Myocyte Glucose homeostasis skeletal muscle Muscle Skeletal Protein kinase B Cells Cultured PI3K/AKT/mTOR pathway Muscle Cells Glucose Transporter Type 4 biology Membrane Proteins Skeletal muscle Lipid metabolism Phosphodiesterase 5 Inhibitors Lipid Metabolism Cell biology 030104 developmental biology medicine.anatomical_structure Insulin Receptor Substrate Proteins biology.protein metabolism tadalafil Phosphodiesterase 5 inhibitor GLUT4 |
| Zdroj: | Endocrine. 59:602-613 |
| ISSN: | 1559-0100 1355-008X |
| Popis: | Tadalafil seems to ameliorate insulin resistance and glucose homeostasis in humans. We have previously reported that tadalafil targets human skeletal muscle cells with an insulin (I)-like effect. We aim to evaluate in human fetal skeletal muscle cells after tadalafil or I: (i) expression profile of I-regulated genes dedicated to cellular energy control, glycolitic activity or microtubule formation/vesicle transport, as GLUT4, PPARγ, HK2, IRS-1, KIF1C, and KIFAP3; (ii) GLUT4, Flotillin-1, and Caveolin-1 localization, all proteins involved in energy-dependent cell trafficking; (iii) activation of I-targeted paths, as IRS-1, PKB/AKT, mTOR, P70/S6K. Free fatty acids intracellular level was measured. Sildenafil or a cGMP synthetic analog were used for comparison; PDE5 and PDE11 gene expression was evaluated in human fetal skeletal muscle cells. RTq-PCR, PCR, western blot, free fatty acid assay commercial kit, and lipid stain non-fluorescent assay were used. Tadalafil upregulated I-targeted investigated genes with the same temporal pattern as I (GLUT4, PPARγ, and IRS-1 at 3 h; HK2, KIF1C, KIFAP3 at 12 h), re-localized GLUT4 in cell sites positively immune-decorated for Caveolin-1 and Flotillin-1, suggesting the involvement of lipid rafts, induced specific residue phosphorylation of IRS-1/AKT/mTOR complex in association with free fatty acid de novo synthesis. Sildenafil or GMP analog did not affect GLUT4 trafficking or free fatty acid levels. In human fetal skeletal muscle cells tadalafil likely favors energy storage by modulating lipid homeostasis via IRS-1-mediated mechanisms, involving activation of I-targeted genes and intracellular cascade related to metabolic control. Those data provide some biomolecular evidences explaining, in part, tadalafil-induced favorable control of human metabolism shown by clinical studies. |
| Databáze: | OpenAIRE |
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