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
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
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
A Single Fibre Approach To The Study Of Regulation Of Protein Synthesis In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$420,039.00
Summary
Skeletal muscle is the most abundant tissue in the human body and accounts for more than 40% of body weight. Loss of muscle mass is a major cause of frailty and loss of functionality in the elderly and is also a common feature of many chronic diseases such as cancer, HIV, arthritis and chronic heart failure. Changes in protein synthesis are intrinsically associated with alterations in muscle mass, which is integral to health, physical performance and independent living. In this project we aim to ....Skeletal muscle is the most abundant tissue in the human body and accounts for more than 40% of body weight. Loss of muscle mass is a major cause of frailty and loss of functionality in the elderly and is also a common feature of many chronic diseases such as cancer, HIV, arthritis and chronic heart failure. Changes in protein synthesis are intrinsically associated with alterations in muscle mass, which is integral to health, physical performance and independent living. In this project we aim to answer some important outstanding questions regarding the regulation of protein synthesis in mammalian skeletal muscle using a novel, single cell approach. Results obtained within the framework of the project will contribute to the understanding of the regulation of cellular and molecular events underpinning protein synthesis in muscle, which is critical for developing effective strategies of treatment and management of various medical conditions to prevent muscle wasting.Read moreRead less
Functional Effects Of Antibodies To Collagen On Cartilage Synthesis And Degradation
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
It has been shown that antibodies to collagen type II in cartilage occur in ~70% of patients with early rheumatoid arthritis, suggesting that autoimmunity to cartilage collagen may play a part in the devleopment of this destructive arthritis. An animal model widely used as a model of human RA is the disease collagen induced arthritis (CIA). It is induced by immunisation of mice with collagen II; antibodies to collagen II are critical for the development of CIA. However not all such antibodies ar ....It has been shown that antibodies to collagen type II in cartilage occur in ~70% of patients with early rheumatoid arthritis, suggesting that autoimmunity to cartilage collagen may play a part in the devleopment of this destructive arthritis. An animal model widely used as a model of human RA is the disease collagen induced arthritis (CIA). It is induced by immunisation of mice with collagen II; antibodies to collagen II are critical for the development of CIA. However not all such antibodies are disease-associated. There may be particular regions on the collagen molecule where antibody-binding causes damage. This project is based on the hypothesis that antibodies to collagen type II, which transfer arthritis in mice, are those that react specifically with regions of the collagen fibrils that are crucial for cartilage stability and function. We plan to test this hypothesis in an in vitro system using cultured cartilage. We predict, based on our preliminary data, that antibodies to collagen II from mice with CIA will interfere with the normal assembly and structure of cartilage. We will test this by adding antibodies under precisely defined conditions to cultured cartilage, and analysing the matrix that is synthesised. The study would then be extended to RA with a comparison of the regions of collagen II that react with antibodies of mouse and human origin. Showing that antibodies to collagen II are directly destructive, allowing for an understanding of their site and mode of action, would greatly advance our understanding of the cause of RA and would lead to more effective forms of treatment.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.