Metabolic Impact of Rapamycin (Sirolimus) and B-Estradiol Using Mouse Embryonic Fibroblasts as a Model for Lymphangioleiomyomatosis

Katherine M. Marsh, David Schipper, Alice S. Ferng, Kitsie Johnson, Julia Fisher, Shannon Knapp, Destiny Dicken, Zain I Khalpey

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Introduction: Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease that predominantly affects women of childbearing age. Exogenous rapamycin (sirolimus) has been shown to improve clinical outcomes and was recently approved to treat LAM, whereas estrogen (E2) is implicated in disease progression. No consistent metabolic model currently exists for LAM, therefore wild-type mouse embryonic fibroblasts (MEF +/+) and TSC2 knockout cells (MEF −/−) were used in this study as a model for LAM. Methods: Oxygen consumption rates (OCR) and redox potential were measured to determine metabolic state across control cells, MEF +/+ and −/− cells treated with rapamycin (Rapa), and MEF +/+ and −/− cells treated with E2. An XF96 extracellular flux analyzer from Seahorse Bioscience® was used to measure OCR, and a RedoxSYS™ ORP was used to measure redox potential. Results: OCR of MEF −/− cells treated with rapamycin (MEF −/− Rapa) versus MEF −/− control were significantly lower across all conditions. The static oxidation reduction potential of the MEF −/− Rapa group was also lower, approaching significance. The coupling efficiency and ratio of ATP-linked respiration to maximum respiration were statistically lower in MEF −/− Rapa compared to MEF +/+ Rapa. There were no significant metabolic findings across any of the MEF cells treated with E2. MEF −/− control cells versus MEF +/+ control cells were not found to significantly differ. Conclusion: MEF cells are thought to be a feasible metabolic model for LAM, which has implications for future pharmacologic and biologic testing.

Original languageEnglish (US)
Pages (from-to)1-6
Number of pages6
JournalLung
DOIs
StateAccepted/In press - Jun 2 2017

Keywords

  • Lymphangioleiomyomatosis
  • Metabolism
  • mTOR
  • Rapamycin
  • Sirolimus

ASJC Scopus subject areas

  • Medicine(all)

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