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Beta-adrenergic agonism protects mitochondrial metabolism in the pancreatectomised rat heart

Published version
Peer-reviewed

Repository DOI


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Authors

Lindsay, Ross T. 
Thisted, Louise 
Zois, Nora E. 
Thrane, Sebastian T. 
West, James A. 

Abstract

The diabetic heart is characterised by functional, morphological and metabolic alterations predisposing it to contractile failure. Chronic sympathetic activation is a feature of the pathogenesis of heart failure, however the type 1 diabetic heart shows desensitisation to β-adrenergic stimulation. Here, we sought to understand the impact of repeated isoprenaline-mediated β-stimulation upon cardiac mitochondrial respiratory capacity and substrate metabolism in the 90% pancreatectomy (Px) rat model of type 1 diabetes. We hypothesised these hearts would be relatively protected against the metabolic impact of stress-induced cardiomyopathy. We found that individually both Px and isoprenaline suppressed cardiac mitochondrial respiration, but that this was preserved in Px rats receiving isoprenaline. Px and isoprenaline had contrasting effects on cardiac substrate metabolism, with increased reliance upon cardiac fatty acid oxidation capacity and altered ketone metabolism in the hearts of Px rats, but enhanced capacity for glucose uptake and metabolism in isoprenaline-treated rats. Moreover, Px rats were protected against isoprenaline-induced mortality, whilst isoprenaline elevated cGMP and protected myocardial energetic status in Px rat hearts. Our work suggests that adrenergic stimulation may be protective in the type 1 diabetic heart, and underlines the importance of studying pathological features in combination when modeling complex disease in rodents.

Description

Acknowledgements: The authors thank Alice Sowton for her contribution to data analysis.

Keywords

Pancreatectomy, Diabetes, Heart, Cardiomyopathy, Mitochondria, Adrenergic

Journal Title

Scientific Reports

Conference Name

Journal ISSN

2045-2322

Volume Title

14

Publisher

Nature Publishing Group UK
Sponsorship
British Heart Foundation (FS/14/59/31282)
Research Councils UK Fellowship (EP/E500552/1)