I am a physiologist investigating the molecular basis of normal function in skeletal muscle and the dysfunctions occurring in various muscle diseases and in fatigue. In addition, I investigate analogous dysfunction of calcium release and excitability occu
Energy Use And Work Output By Cross-bridges In Fast- And Slow-twitch Muscles
Funder
National Health and Medical Research Council
Funding Amount
$191,177.00
Summary
All voluntary movement is produced by the action of skeletal muscles. The muscles provide the mechanical power required to move the limbs and the body. To do so, they require energy which is ultimately derived from the breakdown of food. Therefore, we can describe the fundamental process underlying muscular contraction as the conversion of energy from a chemical form into a mechanical form. This project investigates the relationship between the breakdown of molecules that provide energy and the ....All voluntary movement is produced by the action of skeletal muscles. The muscles provide the mechanical power required to move the limbs and the body. To do so, they require energy which is ultimately derived from the breakdown of food. Therefore, we can describe the fundamental process underlying muscular contraction as the conversion of energy from a chemical form into a mechanical form. This project investigates the relationship between the breakdown of molecules that provide energy and the production of mechanical energy or work. Normal contraction involves many cyclic interactions between two proteins, actin and myosin. Each cycle produces a tiny force that contributes to the shortening of the muscle. For over 30 years, it has been thought that energy required for each force producing cycle was provided by the breakdown of one energy-providing molecule, called ATP. Almost all current models of muscle contraction are based on this idea. Recently, data from studies using isolated actin and myosin and observing their interaction in vitro have indicated that many force-producing cycles may be performed with the energy from just one ATP. If this is correct, it will revolutionise our ideas about the way muscles convert chemical energy into mechanical energy. However, the interaction of proteins in a dish is far removed from a normal muscle and the aim of this project is to determine the relationship between force producing cycles and energy use in intact muscles. If multiple force-producing cycles can be powered by one ATP molecule in intact muscle too, then the current idea that the biochemical processes that release energy from ATP are intimately linked to the mechanical changes in myosin that occur as it produces force will be untenable. In short, we will have to rediscover how muscles convert chemical energy into mechanical energy and find out how that energy can be stored from one force-producing cycle to the next.Read moreRead less
Role Of Calcium Stores And Phosphate Channels In Muscle Fatigue
Funder
National Health and Medical Research Council
Funding Amount
$221,640.00
Summary
Muscles become weaker when ever they are used intensively; this is the familiar muscle fatigue. We are studying the mechanism of muscle fatigue and believe it is caused by depletion of a store of calcium inside the muscle. We suspect the store of calcium declines because phosphate, which is a product of muscle metabolism, enters the calcium store and precipitates as calcium phosphate. Currently we are trying to prove this hypothesis and extend it by studying the channels through which phosphate ....Muscles become weaker when ever they are used intensively; this is the familiar muscle fatigue. We are studying the mechanism of muscle fatigue and believe it is caused by depletion of a store of calcium inside the muscle. We suspect the store of calcium declines because phosphate, which is a product of muscle metabolism, enters the calcium store and precipitates as calcium phosphate. Currently we are trying to prove this hypothesis and extend it by studying the channels through which phosphate passes from the muscle cell into the calcium store. It may be possible to find or design drugs which minimise the movement of phosphate through this channel and such a drug might reduce the component of fatigue caused by this mechanism. Such a drug might benefit patients whose normal activities are limited by muscle fatigue; this includes patients with any disabling muscle disease, such as muscular dystrophy or stroke, and patients with heart failure. In addition elderly people suffer a loss of muscle bulk and the remaining muscle is easily fatigued causing loss of mobility and independence; so the elderly might also benefit from such a drug.Read moreRead less
Mechanisms Regulating Excitation-contraction Coupling In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$687,750.00
Summary
Muscle contraction occurs when an electrical impulse from a nerve travels over the surface of a skeletal muscle fibre and triggers the release of calcium ions from special stores inside the fibre. However, little is known about the regulatory mechanisms involved in turning on and turning off the calcium release. This project investigates the properties of the calcium release and what processes are involved in regulating it. Information about this is vital for understanding how normal muscle work ....Muscle contraction occurs when an electrical impulse from a nerve travels over the surface of a skeletal muscle fibre and triggers the release of calcium ions from special stores inside the fibre. However, little is known about the regulatory mechanisms involved in turning on and turning off the calcium release. This project investigates the properties of the calcium release and what processes are involved in regulating it. Information about this is vital for understanding how normal muscle works and why muscles show reduced performance with exercise (muscle fatigue), with aging, and in certain diseases.Read moreRead less
STRUCTURAL AND FUNCTIONAL INTERACTIONS BETWEEN THE II-III LOOP OF THE SKELETAL DHPR AND THE RYANODINE RECEPTOR
Funder
National Health and Medical Research Council
Funding Amount
$410,250.00
Summary
The project has implications for neuromuscular diseases and for muscle weakness in general and in the elderly, all of which are significant health issues. The results will elucidate molecular mechanisms in muscle contraction and will provide a basis for drug design and treatment of muscle disorders. Respiration and locomotion depend on changes in calcium concentration inside muscle cells. Cardiovascular function, neuronal activity and immune responses also depend on the release of calcium from i ....The project has implications for neuromuscular diseases and for muscle weakness in general and in the elderly, all of which are significant health issues. The results will elucidate molecular mechanisms in muscle contraction and will provide a basis for drug design and treatment of muscle disorders. Respiration and locomotion depend on changes in calcium concentration inside muscle cells. Cardiovascular function, neuronal activity and immune responses also depend on the release of calcium from internal stores. Ryanodine receptor (RyR) calcium channels, either alone or in combination with a different internal calcium channel, regulate calcium release in each of these diverse functions. The essential nature of RyRs is underlined by death at or before birth when RyR expression is defective. Genetic defects in the RyR cause cardiac arrhythmias, malignant hyperthermia and central core disease. RyR function is compromised in heart failure and fatigue. The key role of RyRs makes them a potential therapeutic target, but they are not used as such because of the limited knowledge of the nature and structure of their regulatory sites. Electrical signals from the brain are able to release calcium from internal stores in muscle and initiate muscle contraction by virtue of a physical interaction between two calcium channel proteins, a surface membrane channel and the RyR. The molecular basis of this protein-protein interaction is is not understood and is a subject of this proposal. We will (a) solve the structure of one part of the surface channel that is known to contribute to the protein-protein interaction with the RyR, (b) determine the amino acid residues that interact with each other and (c) evaluate the functional consequences of the the binding of proteins. Understanding more about RyR regulation will pave the way for rational drug design and the eventual use of the RyR as a therapeutic target.Read moreRead less