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The β2-adrenoceptor agonist formoterol attenuates hallmarks of adrenal Cushing's syndrome
Kristan H Cleveland1, Kyung-Soon Lee1, Devasena Ponnalagu1
1Department of Pharmacology, University of Washington, Seattle, Washington, USA.
Background And Purpose:
Signal transduction therapies aim to correct dysregulated cellular signalling pathways implicated in disease. Adrenal Cushing's syndrome, a disorder of excess cortisol production, is frequently driven by somatic mutations in protein kinase A catalytic subunits (PKAc), including PKAcL205R and PKAcW196R.
Experimental Approach:
This study used a combination of in vitro adrenal cell models and an in vivo mouse model harbouring the PKAc W196R mutation to assess the effects of formoterol treatment on mitochondrial function, steroidogenic gene expression and cortisol production. Mitochondrial respiration was evaluated by Seahorse XF analysis and serial block face scanning electron microscopy, and protein expression was measured by western blot and immunohistochemistry.
Key Results:
In this study, we demonstrate that the long-acting β2-adrenoceptor agonist formoterol can be repurposed to manage hypercortisolism. Formoterol significantly attenuates corticosterone secretion in ATC7L adrenal cells expressing Cushing's-associated PKAc variants. In a PKAcWT/W196R mouse model, formoterol treatment alleviates hypercortisolism without inducing adverse cardiovascular effects. Mechanistically, formoterol promotes nuclear translocation of PGC1α, leading to enhanced mitochondrial biogenesis and improved mitochondrial function, as confirmed by Seahorse metabolic analysis. Electron microscopy revealed increased mitochondrial number, volume and structural complexity in adrenal tissue. Analyses of patient samples and adrenal cell lines indicates that formoterol modulates the mitochondrial steroidogenic acute regulatory protein (StAR), suggesting a direct effect on steroidogenesis.
Conclusion And Implications:
These findings support the therapeutic potential of formoterol as a new pharmacological strategy for treating Cushing's syndrome and its associated metabolic comorbidities.
Insights
Formoterol, a repurposed drug, effectively manages hypercortisolism in Cushing's syndrome by improving mitochondrial function and steroidogenesis. This treatment alleviates excess cortisol production without causing cardiovascular side effects.
Area of Science:
- Endocrinology
- Molecular Biology
- Pharmacology
Background:
- Cushing's syndrome is characterized by excess cortisol production, often driven by mutations in protein kinase A catalytic subunits (PKAc).
- Targeting dysregulated cellular signaling pathways is a key strategy for treating such disorders.
Purpose of the Study:
- To investigate the potential of repurposing formoterol, a β2-adrenoceptor agonist, for managing adrenal Cushing's syndrome.
- To assess formoterol's effects on mitochondrial function, steroidogenesis, and cortisol production in relevant models.
Main Methods:
- Utilized in vitro adrenal cell models and an in vivo mouse model with PKAc W196R mutation.
- Assessed mitochondrial respiration via Seahorse XF analysis and electron microscopy.
- Measured protein expression and evaluated cortisol production and steroidogenic gene expression.
Main Results:
- Formoterol significantly reduced corticosterone secretion in cells with Cushing's-associated PKAc variants.
- In a PKAc W196R mouse model, formoterol alleviated hypercortisolism without adverse cardiovascular effects.
- Formoterol enhanced mitochondrial biogenesis and function by promoting PGC1α nuclear translocation and modulating StAR protein.
Conclusions:
- Formoterol demonstrates therapeutic potential as a novel pharmacological approach for Cushing's syndrome.
- These findings support formoterol for treating Cushing's syndrome and associated metabolic comorbidities.
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