Pre-Clinical Studies Identifying Novel Molecular Regulators of Skeletal Muscle Growth and Atrophy

Summary The aim of this project is to use rodent- and cell-based models to examine the potential for specific growth factors, signalling molecules, metabolic enzymes and/or transcription factors to stimulate muscle growth or promote muscle atrophy.

Project Details

Skeletal muscle play fundamental role in the generation of movement and the regulation of whole body metabolism. Muscle mass is lost with prolonged periods of disuse due to injury or immobilization, with diseases such as diabetes, heart disease, cancer, and with ageing. Muscle mass decline can severely impair the ability to perform activities of daily living leading to a further reduction of physical activity and a vicious cycle of inactivity, muscle loss and inactivity-related disease. Thus, strategies aimed at preventing muscle loss and/or promoting muscle growth are essential to limiting disability and preventing disease. Consequently, a thorough understanding of the molecular mechanisms that regulate skeletal muscle mass is crucial to the development of effective exercise programs and potential pharmacological interventions aimed at preventing muscle atrophy/wasting and/or promoting skeletal muscle growth.

The aim of this project is to use rodent- and cell-based models to examine the potential for specific growth factors, signalling molecules, metabolic enzymes and/or transcription factors to stimulate muscle growth or promote muscle atrophy. Genetic gain-of-function (overexpression) and loss-of-function (knockdown) studies will be used, as well as various models of altered physical activity (e.g. immobilization, denervation, mechanical overload) and altered nutrient intake (e.g. food deprivation, protein supplementation). Mechanistic insights into changes in muscle mass will be obtained using molecular analyses that include measures of changes in rates of protein synthesis and protein degradation, the phosphorylation of critical signalling proteins and transcription factors, and gene expression, and the use of DNA-based reporter constructs. Morphological and functional changes will also be examined. This project will include the use of animal surgery, recombinant DNA purification and protein purification, the transfection of muscles in vivo and in cultured cells, Western blotting, immunohistochemistry, microscopy and enzyme activity assays. We aim to report the findings of this project in high impact peer-reviewed scientific journals.