Christopher Thomas Andrew Lewis, MSc, PhD

Novo Nordisk A/S

Title of project

Targeting Skeletal Muscle Myosin for the Treatment of Metabolic Disease

Abstract

Obesity and metabolic disease develop when humans consume more energy than they use. Therefore, successful treatments for metabolic disease must work to counteract this balance by inducing an energy deficit and thus promoting weight loss. To date, no successful target has been identified which can safely and effectively increase energy expenditure. It is essential that this obstacle is overcome to combat the continually growing prevalence in metabolic disease worldwide.

Making up 40% of our overall body mass, skeletal muscle is an obvious organ to target when considering an increase in energy expenditure. Recently, it has been discovered that the structure of skeletal (or cardiac) muscle, particularly the structure of myosin, is a major determinant of the rate of its energy expenditure. When this structure is dysregulated, disease can follow. Critically, myosin has already recently been successfully targeted for the treatment of cardiac disease in which this structure was observed to be aberrant. Furthermore, preliminary data has already observed significant changes to myosin structure in patients with type two diabetes mellitus.

The overarching aim of this project is to establish if myosin would be a suitable target for the treatment of metabolic disease. We aim to investigate the metabolic consequences of manipulations to myosin structure in skeletal muscle using advanced in vitro human skeletal muscle systems and indepth phosphoproteomics. Furthermore, we wish to test novel synthesized compounds which target myosin both in vitro and in vivo as an avenue to treat metabolic disease via increasing resting energy expenditure in skeletal muscle.

If successful, this project has vast implications in not only progressing our understanding of the role of skeletal muscle as a regulator of metabolism but will also highlight a new promising drug target for the treatment of obesity and metabolic disease.

Christopher Thomas Andrew Lewis, MSc, PhD

Industrial fellowship with co-funding from Novo Nordisk A/S

Principal investigator

Christian Pehmøller, Novo Nordisk A/S

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