Abstract
Objectives: Malnutrition is a hallmark of disease in cystic fibrosis (CF). The introduction of elexacaftor/tezacaftor/ivacaftor (ETI) has been associated with increased body mass index (BMI). Preliminary data from a UK cohort study (Igloo-CF), suggests that while BMI increases with ETI therapy, energy intake decreases. We hypothesised that ETI could normalise cellular metabolism in CF, and herein, we assess bioenergetics in two different drug exposed cell models each expressing wild-type (WT) or DF508/DF508 CFTR.
Methods: Human bronchial epithelial cells (HBECs), NuLi-1 WT and CuFi-1 DF508/DF508 and baby hamster kidney cells (BKHs) BHK WT and BHK DF508/DF508 were cultured under basal conditions in the presence of ETI [E (3 µM), T (5/10 µM) and I (2.5/5 µM)] for 48 h. Extracellular acidification rates (ECAR) and oxygen consumption rates (OCR) were measured using XFe96 Extracellular Flux Analyzer. L-lactate secretion and intracellular succinate levels were measured using colorimetric assay kits.
Results: Increased mitochondrial metabolism was found in HBECs and BHK cells expressing the CFTR DF508/DF508 mutation when assessing maximal (p = 0.006) and spare respiratory capacities (p = 0.001). There were significant increases in cellular succinate levels (p
Conclusion: CF cell lines exhibit increased mitochondrial and glycolytic metabolism which can be downregulated by ETI therapy. These changes may impact the energy requirements of patients with CF and provide a partial potential explanation for the paradoxically increased BMI despite falling dietary energy input.
We thank Anil Mehta for critical comments.
Methods: Human bronchial epithelial cells (HBECs), NuLi-1 WT and CuFi-1 DF508/DF508 and baby hamster kidney cells (BKHs) BHK WT and BHK DF508/DF508 were cultured under basal conditions in the presence of ETI [E (3 µM), T (5/10 µM) and I (2.5/5 µM)] for 48 h. Extracellular acidification rates (ECAR) and oxygen consumption rates (OCR) were measured using XFe96 Extracellular Flux Analyzer. L-lactate secretion and intracellular succinate levels were measured using colorimetric assay kits.
Results: Increased mitochondrial metabolism was found in HBECs and BHK cells expressing the CFTR DF508/DF508 mutation when assessing maximal (p = 0.006) and spare respiratory capacities (p = 0.001). There were significant increases in cellular succinate levels (p
Conclusion: CF cell lines exhibit increased mitochondrial and glycolytic metabolism which can be downregulated by ETI therapy. These changes may impact the energy requirements of patients with CF and provide a partial potential explanation for the paradoxically increased BMI despite falling dietary energy input.
We thank Anil Mehta for critical comments.
Original language | English |
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Pages (from-to) | S45 |
Journal | Journal of Cystic Fibrosis |
Volume | 22 |
Issue number | Supplement 2 |
DOIs | |
Publication status | E-pub ahead of print - 9 Jun 2023 |
Event | 46th European Cystic Fibrosis Conference - Austria Center, Vienna, Austria Duration: 7 Jun 2023 → 10 Jun 2023 https://www.ecfs.eu/vienna2023 |