Manipulating Store-operated Ca2+ Entry To Improve Muscle Function In Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$516,163.00
Summary
Muscle function is regulated in a complex manner by calcium and is impaired in Duchenne muscular dystrophy (DMD). Changes in calcium regulation will be investigated in DMD patients and in an animal model using a novel approach. We will use a combination of novel experimental approaches to manipulate muscles in dystrophic mice and test for improvement in function. Results will determine the viability of a potential treatment.
Physiological And Pathological Effects Of Oxidation On Contractile Function In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$613,311.00
Summary
Reactive oxygen molecules generated within muscle fibres in normal exercise and in pathological conditions, greatly affect muscle function by altering the responsiveness of the contractile proteins. This study investigates how various oxidative stresses affect particular reactive sites on key proteins controlling muscle contraction. The findings should identify key molecular changes involved in normal activity and the role oxidation plays in chronic muscle weakness in particular conditions.
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
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
Molecular Basis Of Ca2+-dependent Disruption Of EC-coupling And Weakness In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$530,976.00
Summary
One major cause of weakness in skeletal muscle appears to stem from damage to the mechanism controlling release of calcium ions from internal stores and consequent contraction. This project examines whether the damage is due to excessive levels of intracellular calcium ions activating enzymes that cut a particular vital molecule controlling calcium release. The findings could identify a major factor in muscle weakness in muscular dystrophy and other conditions and lead to specific therapies.
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
Investigating Hippo Signalling As A Novel Cause Of Muscle Disease, And As A Target For New Interventions To Combat Frailty
Funder
National Health and Medical Research Council
Funding Amount
$460,509.00
Summary
We will explore the role of the Hippo signaling pathway in muscle development, repair and remodelling. We propose that this little-known pathway which affects organ development, is key for maintaining healthy muscles, and is affected in muscle wasting. Using gene therapy tools to alter this pathway in models of disease, we intend to clarify the role of Hippo signaling in muscle, and establish whether the pathway can be manipulated to treat physical frailty caused by muscle wasting.
Investigating Follistatin-based Interventions For Long Term-protection Against Frailty Associated With Chronic Illness And Aging
Funder
National Health and Medical Research Council
Funding Amount
$987,169.00
Summary
Effective therapies are urgently needed to combat frailty arising from muscle wasting associated with chronic illness and aging. The proposed studies will investigate the prospects of developing novel short-term interventions that can confer long-term benefits for preventing and treating muscle wasting associated with chronic illness and advanced aging.
Failure-to-progress In Human Labour Results From A Profound Electrical Negativity Of The Uterine Cells: Targeting The Ion Channels Involved
Funder
National Health and Medical Research Council
Funding Amount
$564,541.00
Summary
The incidence of failure to progress in labour has increased in recent years, being linked to the rise in obesity. The result is a significant escalation in the rate of delivery by Caesarean Section (CS) which increases the risk of serious complications during subsequent pregnancies. We have identified dysfunctional systems associated with poor uterine contraction. We now aim to determine the mechanisms underlying these dysfunctional systems to lay the foundations for better therapeutics.