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Endocrine

, Volume 59, Issue 3, pp 602–613 | Cite as

The phosphodiesterase 5 inhibitor tadalafil regulates lipidic homeostasis in human skeletal muscle cell metabolism

  • F. Marampon
  • C. Antinozzi
  • C. Corinaldesi
  • G. B. Vannelli
  • E. Sarchielli
  • S. Migliaccio
  • L. Di Luigi
  • A. Lenzi
  • C. CrescioliEmail author
Original Article

Abstract

Purpose

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.

Methods

RTq-PCR, PCR, western blot, free fatty acid assay commercial kit, and lipid stain non-fluorescent assay were used.

Results

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.

Conclusion

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.

Keywords

PDE5i Tadalafil Insulin Skeletal muscle Metabolism 

Notes

Acknowledgements

This report was supported by ELI Lilly ICOS Corporation, Indianapolis, USA.

Funding

This study was funded by ELI LILLY (Ex NCR H6D-IT-V015).

Compliance with ethical standards

Conflict of interest

Crescioli C declares that she has received research grants from Company ELI LILLY. All the other authors declare that they have no competing interests.

Ethical approval

This article does not contain any studies with animals performed by any of the authors.

Supplementary material

12020_2017_1378_MOESM1_ESM.pdf (997 kb)
Supplementary Information
12020_2017_1378_MOESM2_ESM.pdf (136 kb)
Supplementary Information
12020_2017_1378_MOESM3_ESM.pdf (315 kb)
Supplementary Information

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© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • F. Marampon
    • 1
  • C. Antinozzi
    • 1
  • C. Corinaldesi
    • 1
    • 2
  • G. B. Vannelli
    • 3
  • E. Sarchielli
    • 3
  • S. Migliaccio
    • 1
  • L. Di Luigi
    • 1
  • A. Lenzi
    • 4
  • C. Crescioli
    • 1
    Email author
  1. 1.Department of Movement, Human and Health SciencesUniversità di Roma “Foro Italico”RomeItaly
  2. 2.Leeds Institute of Rheumatic and Musculoskeletal MedicineUniversity of LeedsLeedsUK
  3. 3.Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
  4. 4.Department of Experimental Medicine“Sapienza” University of RomeRomeItaly

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