Targeted Strength Training To Improve Functional Walking Capacity Of Adolescents And Young Adults With Cerebral Palsy
Funder
National Health and Medical Research Council
Funding Amount
$263,449.00
Summary
Cerebral palsy is the most common cause of disability in children. Caused by damage to the brain in early childhood cerebral palsy leads to muscle weakness and difficulties in walking. There is no cure for cerebral palsy, but we can help the weak muscles . The purpose of this trial is to establish that exercises to strengthen the weakest muscles will help the walking ability of teenagers and young adults with cerebral palsy, as they make the transition to independence and adulthood.
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
A RCT Of Power Training And Treadmill Training To Improve Walking Ability In Sub-acute Stroke Patients.
Funder
National Health and Medical Research Council
Funding Amount
$403,041.00
Summary
Stroke causes weakness, incoordination, and reduced aerobic fitness, all of which impact significantly on walking ability and other related functions, such as balance. The current management of stroke patients is inadequate in improving patients' walking ability to a level that promotes independence in the community, as it does not address the impairments at the physiological level necessary to implement significant change. A relatively new approach to walking following stroke is the use of trea ....Stroke causes weakness, incoordination, and reduced aerobic fitness, all of which impact significantly on walking ability and other related functions, such as balance. The current management of stroke patients is inadequate in improving patients' walking ability to a level that promotes independence in the community, as it does not address the impairments at the physiological level necessary to implement significant change. A relatively new approach to walking following stroke is the use of treadmill walking. However, this form of training does not address the weakness following stroke. Therefore we propose to demonstrate the efficacy of a relatively new modality 'treadmill training with power training', at higher intensity over a greater number of sessions than would be received currently with 'usual care' or treadmill training only. To ensure that persons continue to maintain the level of improvement from an intensive exercise program, we will also implement a behavioural change for long-term maintenance of exercise behaviour in a less supervised environment. A randomized, single-blinded, control trial will be used. Subjects will be randomly allocated to 'treadmill training + power training', 'treadmill training', or usual care (i.e. control). Subjects in the two training groups will also receive 'usual care'. Subjects in the treadmill and treadmill + power training groups will attend training sessions for 10 weeks, with 3 sessions per week. Subjects will then be provided with a home exercise package to continue with their exercises. The findings from this study are critical in identifying whether, by addressing the 3 major impairments following stroke at doses which are known to produce physiological change in other frail populations, the stroke patient can achieve independence in walking and walk sufficient distances, both of which are important to the stroke patient.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
Role Of Non-classical Actions Of Androgens In Musculoskeletal Physiology
Funder
National Health and Medical Research Council
Funding Amount
$703,664.00
Summary
Androgens (male sex hormones) are important for growth-maintenance of muscle and bone. The classical action of androgens is to bind the androgen receptor (AR) and regulate target genes. They can also act via non-classical AR mechanisms through other cellular pathways. To understand the role of non-classical actions in the musculoskeletal system we will study mice in which androgens can only act via this pathway. This knowledge is important for the treatment of osteoporosis and muscle wasting.
Testing A Home Based Rehabilitation Program For Survivors Of A Critical Illness: A Randomised Controlled Trial
Funder
National Health and Medical Research Council
Funding Amount
$447,602.00
Summary
The aim of this study is to evaluate whether a home-based, individually tailored physical rehabilitation program can improve the physical and psychological recovery for survivors of a critical illness. Surviving a critical illness results in physical de-conditioning and emotional sequelae. Many observational studies have demonstrated a delayed recovery, often beyond a six-month period. At present there is a lack of specific service provision for the recovering intensive care patient, and prelimi ....The aim of this study is to evaluate whether a home-based, individually tailored physical rehabilitation program can improve the physical and psychological recovery for survivors of a critical illness. Surviving a critical illness results in physical de-conditioning and emotional sequelae. Many observational studies have demonstrated a delayed recovery, often beyond a six-month period. At present there is a lack of specific service provision for the recovering intensive care patient, and preliminary work by us indicates a need for an outreach follow-up service for ICU survivors that does not require individuals to attend an outpatient clinic. The 8-week program includes prescribed training of lower limb exercises, walking, and upper limb exercises, with the goal of improved physical strength and endurance at study end-point of 26 weeks. The standardised leg and arm exercises will be adjusted according to participant progress, using a specifically designed rehabilitation manual. Physical function, endurance and psychological well-being between the usual care and this program will be compared. Importantly, the project addresses outcomes that are clinically meaningful for the patients. It is designed to evaluate whether physical rehabilitation for people recovering from a critical illness improves physical and psychological recovery, which contribute to how people function and they feel. There appears to be little research in this area, so the innovative aspects of the study are an important consideration. The project addresses one of the National Research Priorities using an exercise-based rehabilitation program. It also provides an important innovation: successful implementation and positive findings from this home-based rehabilitation program will provide a model of care that existing primary care or community services can adopt so that all survivors of a critical illness will have the opportunity to improve their physical and psychological recovery.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
Congenital Fibre Type Disproportion (CFTD): Disease Patterns And Pathogenesis Of Muscle Weakness
Funder
National Health and Medical Research Council
Funding Amount
$264,816.00
Summary
Congenital Fibre Type Disproportion (CFTD) is a type of genetic muscle disease that is caused by changes (mutations) in several different genes. Affected children usually have general muscle weakness from birth. We will compare medical findings and muscle MRI scans in different CFTD patients to develop guidelines for the care and diagnosis of CFTD patients. We will also study how gene mutations lead to weakness and the abnormalities seen on the muscle biopsy, focusing on the TPM3 gene.
The Molecular Mechanisms Of Anabolic Androgen Actions In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
We are studying the role of male sex hormones, androgens, in controlling muscle function. Muscle wasting occurs in a variety of disorders, including cancer, burns and trauma, and also during normal ageing. Treatment with androgens helps prevent muscle wasting, and causes increased muscle size, although current therapies can also have side effects. Little is known about how androgens prevent wasting and promote muscle growth. Therefore, we propose to study the actions of male sex hormones in musc ....We are studying the role of male sex hormones, androgens, in controlling muscle function. Muscle wasting occurs in a variety of disorders, including cancer, burns and trauma, and also during normal ageing. Treatment with androgens helps prevent muscle wasting, and causes increased muscle size, although current therapies can also have side effects. Little is known about how androgens prevent wasting and promote muscle growth. Therefore, we propose to study the actions of male sex hormones in muscle. We will study the growth of mouse muscle cells in culture, and measure their rate of growth when treated with androgens. All cells contain certain factors that control their growth and replication, and we will test whether androgens activate these factors to increase growth. We will also study the effect of androgens on muscle in mice, to investigate complex effects that only occur in real muscle. We will neuter male mice, which causes muscle wasting. Neutered mice will then be treated with androgens or placebo, and we will compare the muscle growth effect of androgen treatment versus placebo. We will measure muscle strength, size, and the number of muscle cells in treated and placebo mice. We will also see if the effects of androgen require a particular protein, the androgen receptor, which acts as a lock-key mechanism in cells, to allow them to respond to androgens. We will make a strain of mouse with a non-functional version of the androgen receptor only in muscle cells. This will determine if the muscle growth effects of androgens occur through a direct action on muscle, or indirectly through acting on other tissues in the body. This information will ultimately allow us to design more targeted androgen therapies for muscle wasting, that act only on muscle.Read moreRead less
SPECIFIC MODIFICATION OF SKELETAL MUSCLE RYANODINE RECEPTOR ACTIVITY
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
The project will have implications for muscle fatigue, which is a public health issue in an aging population, and for neuromuscular diseases and muscle weakness. The ryanodine receptor (RyR) calcium release channel regulates changes in calcium concentrations inside the muscle cell that are essential for respiration and movement. Defects in expression of RyRs results in death in utero or at birth. The RyR is also important in many other tissues, where it acts either alone or in combination with a ....The project will have implications for muscle fatigue, which is a public health issue in an aging population, and for neuromuscular diseases and muscle weakness. The ryanodine receptor (RyR) calcium release channel regulates changes in calcium concentrations inside the muscle cell that are essential for respiration and movement. Defects in expression of RyRs results in death in utero or at birth. The RyR is also important in many other tissues, where it acts either alone or in combination with a second type of calcium channel, to regulate the changes in the concentrations of calcium ions within the cell, which are essential for a variety of processes including cardiac contraction, vascular constriction, neuronal activity and immune responses. Despite its importance, little is known about the regulation of the RyR channel opening during contraction in skeletal muscle or the mechanisms of ion movement through its pore. It is often difficult to define the specific role of RyRs in intact tissues because of the lack of specific probes for the channel. The RyR is an obvious target for therapeutic drugs to modify muscle contraction, but has not been used as such because of the lack of specific and reversible drugs. Muscle performance is reduced, and fatigue is rapid, in neuromuscular disease. Performance can be improved by variety of drugs like anabolic steroids which unfortunately have additional adverse actions. The aims of the project are (a) to discover more about the regulation of, and ion conduction pathway through, the skeletal muscle RyR channel, (b) to identify compounds that can be used as specific probes for RyR activity and (c) to identify compounds that might in the future provide the basis for development of the RyR as a therapeutic target.Read moreRead less