Maintenance of skeletal muscle integrity is critical for normal locomotor function. During adulthood skeletal muscle mass and strength is progressively lost which leads to locomotor impairment common in the elderly. Loss of skeletal muscle may also contribute to functional impairment in patients with inherited disorders of the scaffolding connective tissue that hold muscle fibres together, such as Duchenne's dystrophy. Understanding the biology of muscle cell growth and responses to environmenta ....Maintenance of skeletal muscle integrity is critical for normal locomotor function. During adulthood skeletal muscle mass and strength is progressively lost which leads to locomotor impairment common in the elderly. Loss of skeletal muscle may also contribute to functional impairment in patients with inherited disorders of the scaffolding connective tissue that hold muscle fibres together, such as Duchenne's dystrophy. Understanding the biology of muscle cell growth and responses to environmental stresses such as exercise and ageing is, therefore, critical to healthy daily functioning. In preliminary studies we have defined a novel biochemical pathway which we believe underlies the ability of muscle to grow larger and stronger. In this application, we propose to rigorously evaluate the role of this pathway in muscle growth by experiments performed both with cell culture models and in animals. The findings of this study would have direct therapeutic benefit for a large number of major clinical conditions, such as heart failure, age-related muscular weakness and muscle diseases.Read moreRead less
Characteristics Of Splice Variants Of The Skeletal Muscle Ryanodine Receptor: Implications For Myotonic Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$258,000.00
Summary
The project is to address some of the basic molecular changes that occur in skeletal muscle during development and in myotonic dystrophy. Myotonic dystrophy is a significant health issue since it is the most common adult muscular dystrophy, with an occurrence of ~1 in 7000. The results will provide much needed information about the membrane-associated molecular mechanisms that regulate muscle contraction and may provide a basis for drug design and treatment of myotonic dystrophy. Respiration and ....The project is to address some of the basic molecular changes that occur in skeletal muscle during development and in myotonic dystrophy. Myotonic dystrophy is a significant health issue since it is the most common adult muscular dystrophy, with an occurrence of ~1 in 7000. The results will provide much needed information about the membrane-associated molecular mechanisms that regulate muscle contraction and may provide a basis for drug design and treatment of myotonic dystrophy. Respiration and locomotion depend on the release of calcium ions from stores inside muscle cells. Ryanodine receptor calcium channels regulate calcium release from the stores. The essential nature of ryanodine receptors is underlined by death at or before birth when ryanodine receptor expression is defective. In addition genetic defects in the ryanodine receptor cause cardiac arrhythmias, malignant hyperthermia and central core disease. Ryanodine receptor function is compromised in heart failure and fatigue. The essential role of ryanodine receptors makes them a potential therapeutic target, but they are not used in this way because of our limited knowledge of the protein. Myotonic dystrophy is an autosomal dominant multi-system disorder, in which an expansion of non-coding DNA leads to changes in expression of several different proteins. Although the genetic basis of myotonic dystrophy is now reasonably well understood, the contribution of molecular changes in the affected proteins to the myopathy has not been investigated. Our group has recently discovered that the juvenile form of the ryanodine receptor protein is highly expressed in adults suffering from myotonic dystrophy. By discovering more about the properties of the juvenile isoform, we will understand more about the basic mechanisms of ryanodine receptor function in developing muscle and in myotonic dystrophy and be able to design drugs to specifically modify ryanodine receptor activity.Read moreRead less
The Role Of Notch Signalling In Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy, caused by a lack of a protein called dystrophin. Dystrophic muscles are fragile, prone to injury, and have a compromised ability to regenerate after damage. Defective Notch signalling has been implicated in the poor regenerative response of aged muscles and similarly in dystrophy based on our preliminary data. Modulating Notch signalling could therefore delay the onset or slow the progression of DMD.
Excitation-contraction Coupling In Skeletal Muscle In Health, Exercise And Disease
Funder
National Health and Medical Research Council
Funding Amount
$623,621.00
Summary
Skeletal muscle dysfunction occurs in certain diseases, aging and exercise, and can deleteriously affect lifestyle and mobility. This project investigates the molecular mechanisms involved in the complex sequence of events that occur in each individual muscle fibre, starting from stimulation by a nerve through to the fibre contracting. This should give information about causes of skeletal muscle dysfunction in myotonia, heart failure and other situations, and help development of therapies.
The Role Of Dysferlin In Muscular Dystrophy And Skeletal Muscle Membrane Repair.
Funder
National Health and Medical Research Council
Funding Amount
$316,667.00
Summary
Patients who lack the protein dysferlin have muscular dystrophy. These patients are unable to repair their muscle membranes, which get damaged during normal activities. A defect in membrane repair is a new pathway implicated in the muscular dystrophies, and it is likely that other patients will also have defective muscle membrane repair. We will find out how dysferlin mediates its role in membrane repair, and identify other dysferlin-interacting proteins, as these may also underlie disease.
Targeting The TGF-beta Signalling Pathway To Improve Muscle Growth And Development In Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy. Dystrophic muscles are fragile, prone to injury, and do not regenerate well after injury. Modulating cell signalling pathways that are involved in muscle growth has the potential to attenuate the severity of the dystrophic pathology, to delay the onset or slow the progression of the muscle wasting and weakness, and to improve muscle growth and development in muscular diseases.
Molecular Mechanisms Of Photoreceptor Protection In Rat Models Of Degenerative Retinal Disease
Funder
National Health and Medical Research Council
Funding Amount
$277,480.00
Summary
The photoreceptor cells of the eye (rods and cones) are the cornerstones of vision. Without them the complex and rich sense of vision fades into blindness. In 1 person in 4-5,000 - about 5,000 Australians and 1-2 million people world-wide - these cells degenerate spontaneously. The condition which results is known as retinitis pigmentosa (RP); it causes progesses blindness, most often affecting young adults. Despite recent advances in research, there is still no effective cure. The present work ....The photoreceptor cells of the eye (rods and cones) are the cornerstones of vision. Without them the complex and rich sense of vision fades into blindness. In 1 person in 4-5,000 - about 5,000 Australians and 1-2 million people world-wide - these cells degenerate spontaneously. The condition which results is known as retinitis pigmentosa (RP); it causes progesses blindness, most often affecting young adults. Despite recent advances in research, there is still no effective cure. The present work will explore the environmental factors which determine whether photoreceptors last the lifetime of the individual, or die prematurely. The factors which cause their premature death include genetic mutations but also include environmental factors, including the oxygen status of the retina, the brightness of light experienced and the retina's response to stress. We will investigate the mechanisms by which the retina protects photoreceptors in the face of stress, and how it prepares itself for future insults. Several of these mechanisms have already been identified. The present work will investigate their function at the molecular level, to gain the understanding need to influence their operation. Understanding the response of photoreceptors to these environmental stresses will make it possible to slow the degeneration by manipulating the retinal environment.Read moreRead less