Regulatory mechanisms in skeletal muscle lipid hydrolysis. The regulation of intramuscular triglyceride (fat) utilisation by human skeletal muscle is largely unknown. Our contention is that the specialized protein enzyme, hormone sensitive lipase (HSL), has a fundamental role in intramuscular triacylglycerol utilisation and is regulated by both intramuscular levels of key metabolites and circulating hormone concentrations. We also propose control points subsequent to HSL activation are important ....Regulatory mechanisms in skeletal muscle lipid hydrolysis. The regulation of intramuscular triglyceride (fat) utilisation by human skeletal muscle is largely unknown. Our contention is that the specialized protein enzyme, hormone sensitive lipase (HSL), has a fundamental role in intramuscular triacylglycerol utilisation and is regulated by both intramuscular levels of key metabolites and circulating hormone concentrations. We also propose control points subsequent to HSL activation are important for triglyceride hydrolysis. Our proposed project examines these factors and will enhance our understanding of the regulation of muscle fat use, thereby leading to potential metabolic strategies (nutritional, pharmacological) that enhance skeletal muscle function at rest and during exercise.Read moreRead less
Biological Role of Contraction-Induced Heat Shock Protein Expression. It is well known that mammalian skeletal muscle increases its expression of a group of highly conserved proteins, the heat shock proteins (HSP) in response to repeated contraction. However, the biological role of this expression is unclear. The aim of this project is to determine the biological role of contraction-induced HSP expression. We expect to show that HSP synthesis in response to exercise has three major roles; 1) to ....Biological Role of Contraction-Induced Heat Shock Protein Expression. It is well known that mammalian skeletal muscle increases its expression of a group of highly conserved proteins, the heat shock proteins (HSP) in response to repeated contraction. However, the biological role of this expression is unclear. The aim of this project is to determine the biological role of contraction-induced HSP expression. We expect to show that HSP synthesis in response to exercise has three major roles; 1) to act to repair damaged proteins in recovery from muscle injury 2) to act as a "molecular motor" to translocate proteins from one region of a muscle cell to another and 3) to be released into the circulation in order to act as a central signal to activate immune cells. Such a project will be significant because it will allow for a fundamental understanding as to why these proteins are produced in response to exercise. We expect to enhance our understanding of fundamental cell biology.Read moreRead less
Reducing the fat burden: Identification of novel cellular and molecular targets for alleviating skeletal muscle insulin resistance. Insulin resistance and the associated consequences are a major public health problem in Australia and cost the healthcare system >$1.1 billion/year. Exercise training and thiaziolidinedione (TZD) treatment are therapies that partially ameliorate insulin resistance through distinct and independent mechanisms. However, neither intervention represents a viable long-ter ....Reducing the fat burden: Identification of novel cellular and molecular targets for alleviating skeletal muscle insulin resistance. Insulin resistance and the associated consequences are a major public health problem in Australia and cost the healthcare system >$1.1 billion/year. Exercise training and thiaziolidinedione (TZD) treatment are therapies that partially ameliorate insulin resistance through distinct and independent mechanisms. However, neither intervention represents a viable long-term strategy: exercise training has low compliance, while chronic TZD use is associated with several adverse side effects (edema, weight gain etc.). We will investigate the metabolic, cellular and molecular mechanisms by which these therapies each exert their positive effect on insulin action with the aim of identifying novel targets for future drug interventions. Read moreRead less
Regulation Of Protein Kinases And Their Substrates
Funder
National Health and Medical Research Council
Funding Amount
$553,197.00
Summary
Our research is concerned with the control of the body's energy metabolism via an enzyme called AMPK. This enzyme is at the hub of metabolic control in response to diet and exercise. AMPK controls energy expenditure in response to demand as well as appetite. It is well recognized that diet and sedentary life-styles are major contributors to obesity and cardiovascular disease. We are testing how a new drug activates AMPKand how energy expenditure can be increased.
Function And Pathophysiological Role Of A Novel Glucose Transporter Expressed In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$216,412.00
Summary
Diabetes is a disorder of metabolism resulting from a combination of deficiency of insulin and defective action of the insulin that is present. The most prominent metabolic abnormality is high blood glucose, which is often not satisfactorily corrected by insulin treatment. One of the main reasons for the high blood glucose is reduced uptake of glucose by muscle tissue. The mechanism by which insulin enhances glucose entry into muscle cells involves mobilisation of a specific protein from the glu ....Diabetes is a disorder of metabolism resulting from a combination of deficiency of insulin and defective action of the insulin that is present. The most prominent metabolic abnormality is high blood glucose, which is often not satisfactorily corrected by insulin treatment. One of the main reasons for the high blood glucose is reduced uptake of glucose by muscle tissue. The mechanism by which insulin enhances glucose entry into muscle cells involves mobilisation of a specific protein from the glucose transporter protein family, which has been designated GLUT4. Surprisingly, animals that have been genetically altered to eliminate orknockout GLUT4 production do not develop diabetes. This finding has led to the theory that there is a backup glucose transporter protein that can prevent diabetes when there is a problem with GLUT4 function. We have recently discovered a new member of the glucose transporter protein family that could potentially function as either a parallel or a backup system for GLUT4. This new glucose transporter, which we have called GLUT8, is present in human muscle tissue and studies in other cells have shown that it alters its distribution within the cell in reponse to insulin. We now want to study in more detail the role of this new glucose transporter in muscle tissue and how it functions compared with GLUT4. In particular, we think it is possible that Type 2 diabetes occurs when there is not only a problem with the mobilisation of GLUT4 but also a defect in the production or function of GLUT8. If this is the case, then increasing GLUT8 production might improve glucose transport into muscle tissue and so improve control of blood glucose levels in diabetes.Read moreRead less
Molecular networks underlying mitochondrial biogenesis in humans. Mitochondria are essential for life, and we propose a highly-innovative approach (employing multiple, cutting-edge ‘omic’ technologies and bioinformatics) to advance the fundamental understanding of how mitochondria respond and adapt to exercise in humans. The project outcomes should include significant new knowledge and advanced expertise that can be used by others to facilitate additional research outcomes. The project anticipa ....Molecular networks underlying mitochondrial biogenesis in humans. Mitochondria are essential for life, and we propose a highly-innovative approach (employing multiple, cutting-edge ‘omic’ technologies and bioinformatics) to advance the fundamental understanding of how mitochondria respond and adapt to exercise in humans. The project outcomes should include significant new knowledge and advanced expertise that can be used by others to facilitate additional research outcomes. The project anticipates the contribution of innovative tools for molecular biology research, benefiting therapeutic and biotechnology applications. This project will support advanced training of young researchers in frontier technologies, which will expand Australian research capabilities and help produce a higher quality workforce.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE140100864
Funder
Australian Research Council
Funding Amount
$394,334.00
Summary
Discovering The Effect of alpha-actinin-3 Deficiency on Muscle Adaptations to Exercise Training in Humans. The protein alpha-actinin-3 is expressed in fast muscle fibres. A common gene variant results in complete deficiency in alpha-actinin-3 that has been shown to influence athletic performance. A mouse model has been previously generated to demonstrate that alpha-actinin-3 deficiency results in a significant shift in fast muscle fibres, towards the slow, more efficient muscle fibres. This proj ....Discovering The Effect of alpha-actinin-3 Deficiency on Muscle Adaptations to Exercise Training in Humans. The protein alpha-actinin-3 is expressed in fast muscle fibres. A common gene variant results in complete deficiency in alpha-actinin-3 that has been shown to influence athletic performance. A mouse model has been previously generated to demonstrate that alpha-actinin-3 deficiency results in a significant shift in fast muscle fibres, towards the slow, more efficient muscle fibres. This project will demonstrate the effects of alpha-actinin-3 deficiency on the characteristics of human muscle pre and post exercise training. Outcomes will include major applications for personalising health recommendations and in designing preventative programs for ageing.Read moreRead less