Role Of Nitric Oxide And Reactive Oxygen Species In Excitation-contraction Coupling In Skeletal Muscle.
Funder
National Health and Medical Research Council
Funding Amount
$163,250.00
Summary
Excitation-contraction (E-C) coupling is a term used to broadly describe the sequence of cellular events that starts with an electrical signal at the surface membrane of a muscle cell and which then ultimately leads to muscle contraction. Although the overall sequence is known, there remain many gaps in our understanding of the mechanisms involved not only related to normal muscle function but to how this function may be impaired by excessive exercise and disease. Many cellular metabolites contr ....Excitation-contraction (E-C) coupling is a term used to broadly describe the sequence of cellular events that starts with an electrical signal at the surface membrane of a muscle cell and which then ultimately leads to muscle contraction. Although the overall sequence is known, there remain many gaps in our understanding of the mechanisms involved not only related to normal muscle function but to how this function may be impaired by excessive exercise and disease. Many cellular metabolites contribute towards the normal control of muscle contraction, while others contribute to its impairment. Reactive oxygen species (ROS), which includes nitric oxide (NO) and related molecules, are metabolic factors often referred to as cellular oxidants. They are thought to have an essential role in controlling normal muscle function. Paradoxically, they are also implicated in the impairment of muscle function associated with fatigue, disease and aging. How these molecules both control normal muscle activity and also contribute to impairment of such function remains unclear. Thus, the central aim of this project is to identify the mechanisms by which the cellular oxidants, NO and other ROS, both control normal E-C coupling in skeletal muscle fibres and how they contribute to muscle fatigue. Clearly, understanding how skeletal muscle normally contracts is essential in order to better understand how muscle function can become impaired with exercise, disease and age. The work from this study will provide insight into both normal muscle physiology and how muscles fatigue and ultimately provide new methodologies and drugs that may combat fatigue, disease and age related changes to muscle function.Read moreRead less
TEMPERATURE AS MODIFIER OF MAMMALIAN SKELETAL MUSCLE FUNCTION AND OF MUSCLE RESPONSIVENESS TO PHYSIOLOGICAL FACTORS
Funder
National Health and Medical Research Council
Funding Amount
$256,018.00
Summary
Contracting muscles are a major source of heat production in the body. Heat produced by contracting muscles can cause muscle damage if muscle temperature increases above 44oC. Also, overheating from external sources can cause an increase in muscle temperature in the upper physiological range of temperature (37-44oC) which can so readily happen to humans and animals caught in blistering sun or in closed cars parked in the sun. However, very little is known about what happens to the ability of the ....Contracting muscles are a major source of heat production in the body. Heat produced by contracting muscles can cause muscle damage if muscle temperature increases above 44oC. Also, overheating from external sources can cause an increase in muscle temperature in the upper physiological range of temperature (37-44oC) which can so readily happen to humans and animals caught in blistering sun or in closed cars parked in the sun. However, very little is known about what happens to the ability of the skeletal muscle to contract when the temperature increases in this upper physiological range of temperature. This project seeks to fill in this important gap in our knowledge and increase our understanding about the existence of protective mechanisms in muscle to prevent heat-induced damage to the muscle. Such mechanisms would allow the body to operate very close to the lethal range of temperature and may be mainly responsible for the severe muscle weakness in overheated individuals. Results obtained from the project can have far reaching implications for human physiology in general and muscle and exercise physiology in particular and for developing new strategies in the treatment of collapse from body overheating. The project will also produce new knowledge regarding the mechanism of action of drugs used in the treatment of certain mental disorders but which can trigger, in susceptible individuals, uncontrolled contraction of muscles and overheating.Read moreRead less
Investigation Of The Roles Of Calcium-dependent Proteases In Muscle Damage And Disease
Funder
National Health and Medical Research Council
Funding Amount
$360,160.00
Summary
Muscle strength is important to the health and well-being of everyone. Skeletal muscle weakening occurs as a result of certain disease states, aging and prolonged inactivity due to illness-injury-surgery. This can result in the loss of normal activity and mobility and an increased incidence of falls and accidents, which impact considerably on health care costs. There is a family of proteins called calpains that have been linked to a number of factors affecting muscle function, however it is not ....Muscle strength is important to the health and well-being of everyone. Skeletal muscle weakening occurs as a result of certain disease states, aging and prolonged inactivity due to illness-injury-surgery. This can result in the loss of normal activity and mobility and an increased incidence of falls and accidents, which impact considerably on health care costs. There is a family of proteins called calpains that have been linked to a number of factors affecting muscle function, however it is not known how they are involved. Calpains are proteases, ie. they destroy other proteins, and they are regulated by the concentration of calcium inside a cell. The calcium concentration increases dramatically inside a muscle cell when it contracts. Inside a muscle cell it is important that there is tight regulation of the calpains to avoid them being activated inappropriately during normal use and causing muscle damage. In certain disease states, such as types of muscular dystrophy, it is known that the calcium concentration within resting muscle fibres is increased compared with healthy muscle fibres. We propose that as a consequence of this, the calpains will be less regulated and will cause damage to the muscle, which contributes to the muscle weakness seen in these diseases. Whilst calpains have been implicated with symptoms associated with muscle dystrophies, the role they play is certainly unclear. The objectives of our research proposal are to understand what factors influence i) where the calpains are located and ii) when and how much they are activated, within muscle fibres. We will compare this in healthy muscle and muscle from mdx mice, an animal model of Duchenne muscular dystrophy.Read moreRead less
The Influence Of A-actinin-3 On Muscle Structure, Metabolism, Performance And Response To Diet And Disease
Funder
National Health and Medical Research Council
Funding Amount
$624,355.00
Summary
We have identified a common genetic variant that results in absence of the fast muscle fibre protein a-actinin-3 in more than one billion humans worldwide. Loss of a-actinin-3 influences elite athletic performance, muscle bulk and strength in the general population, response to diet and exercise, and susceptibility to developing type 2 diabetes. We will now study mice and humans to determine how this gene influences variations in human performance, metabolism and severity of muscle disease.
BioPolymer Fibres For Remodelling Mdx And Damaged Muscle
Funder
National Health and Medical Research Council
Funding Amount
$527,286.00
Summary
This project aims to generate new, smart polymers for use in re-building muscle that has degenerated due to disease and-or trauma damage. The merger of smart polymers with biologically based solutions and cells has great potential to improve outcomes of treatments of damaged muscle in diseases such as Muscular Dystrophy.
Regulatory Mechanisms And Roles Of Calpains In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$439,813.00
Summary
The objectives are to understand the regulation and roles of calpains, which are proteases that break proteins in the building and repair of skeletal muscle. We will determine targets that calpains cleave and whether their location changes following activation, as well as the cellular factors regulating their activity. In addition, we will obtain information about the specific type of calpain dysfunction that occurs in particular patients with limb girdle muscular dystrophy 2A.
NEURAL MODULATION OF HEARING LOSSES INDUCED BY LOUD SOUND
Funder
National Health and Medical Research Council
Funding Amount
$290,500.00
Summary
Loud sounds, from occupational and recreational sources, are the most common threat to hearing and can result in temporary hearing losses (as might be experienced after an evening at a noisy pub or concert) or permanent hearing losses (after prolonged or multiple loud sounds, as for example in a noisy work environment). Noise reduction programs are either not always possible or effectively applied. A parallel strategy is the study of biological mechanisms that may ameliorate hearing damage, with ....Loud sounds, from occupational and recreational sources, are the most common threat to hearing and can result in temporary hearing losses (as might be experienced after an evening at a noisy pub or concert) or permanent hearing losses (after prolonged or multiple loud sounds, as for example in a noisy work environment). Noise reduction programs are either not always possible or effectively applied. A parallel strategy is the study of biological mechanisms that may ameliorate hearing damage, with a view to optimising such mechanisms. I propose to build on seminal Australian work to examine how one such system, nerves from the brain to the inner ear (the site of most damage from loud sounds), modulates hearing losses caused by loud sounds. Early studies indicated these nerves could protect from damage induced by short-lasting loud sound and this has led to international interest in functional applications of such protection to reduce hearing damage suffered by humans. However, my recent work indicates the nerves exert complex protective and exacerbative effects to loud sounds similar to common trauma or occurring under conditions similar to common trauma. They even exacerbate hearing losses due to loud sound, especially when there is an imbalance in hearing sensitivity in the two ears (bilateral) similar to what is common in humans. These findings make it critical that functional application be delayed until the full range of effects exerted by the nerves is understood. I propose to elucidate the novel complex effects of these nerves to loud sound. Specific aims are: (1) To understand effects of these pathways to loud sounds like those encountered by humans, (2) To investigate how chronic imbalanced bilateral hearing sensitivity, like that common in humans, alters effects of the nerves and when they change from being protective to exacerbative, (3) To adduce how an atraumatic sound affects hearing losses due to later loud sound and the role played by these nerves.Read moreRead less