Maithily Satish Nanadikar - Postdoctoral Fellowship 2023
Project summary:
Translating molecular mechanisms regulating obesity and exercise-linked cardiac metabolism using more human-like iPSC and porcine models
Hypotheses:
1. Decreased GLUT4-dependent glucose uptake and metabolism contributes is an early and causative instigator of obesity and diabetes-linked cardiomyopathy
2. Human cardiac muscle metabolism is regulated by the same cell signalling mechanisms identified in rodent striated muscle
3. GLUT4 is mis-localized in the obese, insulin-resistant adult pig heart compared to lean controls and associated with altered mitochondrial redox status
4. Mitochondrial oxidative stress is necessary and sufficient to disrupt GLUT4 trafficking on microtubules in human cardiac muscle cells.
Project Title
Translating molecular mechanisms regulating obesity and exercise-linked cardiac metabolism using more human-like iPSC and porcine models
Background
Daily living requires the human heart to match cardiac output to varying external demands. Glucose uptake and metabolism are likely essential to the normal function of the heart. Insulin and contraction-stimulated translocation of glucose transporter (GLUT)4 from intracellular compartments to the cell surface facilitates the glucose uptake into cardiomyocytes. Studies in mainly rodents suggest that decreased GLUT4- dependent glucose uptake may contribute to early obesity-linked cardiomyopathy, with some studies suggesting a therapeutic benefit of reestablishing glucose uptake. These mechanisms clearly deserve further exploration in models closer to the human heart.
Aim
1. To establish metabolically mature iPSC CM model to clarify how GLUT4 translocation is regulated by electrical pacing and insulin in cells of human origin compared to mice.
2. To describe GLUT4 and redox protein expression and localization changes at early stages of obesityassociated cardiomyopathy in a large-animal pig model.
3. To establish the mechanism by which mitochondrial oxidative stress impairs GLUT4 trafficking in iPSCCMs.
Maithily Satish Nanadikar
- MTech and PhD
- University of Copenhagen, Department of Nutrition, Exercise and Sports
Principal and co-principal investigators:
Main PI- Thomas E. Jensen, Associate professor, University of Copenhagen
Co-PI 1- Daniel Fazakerley, Senior Research Associate, University of Cambridge
Co-PI 2- Guilia Borghetti, PhD, Novo Nordisk
Collaborators:
Christian Pehmøller, Novo Nordisk, Denmark
Andreia Bernardo, Francis Crick Institute, UK
Berit Christoffersen, Novo Nordisk, Denmark
Johan Lind, Technical University of Denmark