Identification Of The Molecular Mechanisms By Which Mutations In FHL1 Lead To Protein Misfolding And Skeletal Muscle Disease
Funder
National Health and Medical Research Council
Funding Amount
$609,424.00
Summary
Skeletal muscle diseases result in debilitating muscle loss and may result from an error (mutation) within a gene. Mutations in FHL1 were identified as the cause of four different muscle diseases. Using purified FHL1, skeletal muscle cells and animal models we will investigate how FHL1 mutations cause muscle wasting, and loss of muscle strength.
Decrypting The Excitation Contraction Coupling Machinery In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$914,869.00
Summary
Skeletal muscle function is dependent upon the fine control of calcium levels. When communication of key proteins in muscle are compromised, calcium levels are uncontrolled leading to severe disabilities. The molecular pathways that control signalling between key muscle proteins is currently unknown and shedding light on this topic will aid in the discovery of therapies for muscle-associated disabilities in disease and with aging.
Molecular Genetic Characterisation Of A Novel X-linked Skeletal Myopathy
Funder
National Health and Medical Research Council
Funding Amount
$158,104.00
Summary
This project aims to identify the genetic basis of a new disease that is characterised by episodes of muscular weakness. This disease only affects males. The signficance of the project is that this is the first description of such a disorder and gives us an opportunity to study a previously unsuspected aspect of human muscle function.
Novel Transcriptional Regulation In Skeletal Muscle Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$344,592.00
Summary
It has been assumed that once genes are activated in a particular type of cell, they remain 'on'. From work described in this laboratory, we now know that gene activity may come and go. Instead of the analogy of a light switch that has been turned on and stays on, it appears that at least in muscle, gene activity is more like blinking lights. If you take an image of muscle tissue, which is just a snapshot in time, a gene may not appear to be activated if it was temporarily 'flashing off' at the ....It has been assumed that once genes are activated in a particular type of cell, they remain 'on'. From work described in this laboratory, we now know that gene activity may come and go. Instead of the analogy of a light switch that has been turned on and stays on, it appears that at least in muscle, gene activity is more like blinking lights. If you take an image of muscle tissue, which is just a snapshot in time, a gene may not appear to be activated if it was temporarily 'flashing off' at the time of viewing. This may occur in all tissue types, but it is more easily detected in muscle because the cell is large with many nuclei, rather than small with a single nucleus. Another reason why this phenomenon is more readily detectable in muscle cells is that they are very dynamic cells that can undergo fairly radical changes in shape. An actively growing or hypertrophying muscle cell may have all of its genes at a high pitch of transcriptional activity to support rapid growth. However, once a muscle cell has reached its appropriate size, then muscle genes switch to a flashing mode of transcription to maintain rather than build structures. SIGNIFICANCE: (1) This may be a fundamental mechanism of gene regulation that occurs in virtually all cell types. As such, our finding will open an area of research into the types of molecules involved in this novel mechanism. (2) Our studies will result in a better understanding of the mechanisms of muscle cell hypertrophy in response to excercise and drugs, as well as atrophy due to nerve damage or inherited muscle disease. (3) This mechanism may explain the expression of foreign DNA in muscle cells delivered via gene therapy approaches. Our findings could result in a more efficacious means of expressing the introduced gene that might require tricking the muscle fibre into believing that it is in a perpetual growth mode.Read moreRead less
IGF-1 AS A THERAPEUTIC AGENT: HOW DOES IGF-1 AFFECT OXIDATIVE STRESS IN DYSTROPHIC AND AGED SKELETAL MUSCLE?
Funder
National Health and Medical Research Council
Funding Amount
$545,243.00
Summary
Loss of skeletal muscle mass (wasting) and function occurs in many clinical conditions, including muscular dystrophy, neuromuscular and inflammatory disorders, and also normal ageing. A growth factor (IGF-1) is a promising therapeutic as it increases protein synthesis. Muscle wasting (loss of protein) is also associated with increased oxidative stress. The project will evaluate the impact of IGF-1 on oxidative stress using genetically engineered mouse models of muscular dystrophy and ageing.
A Novel Cytoskeletal Structure In Muscle Is Associated With Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$371,250.00
Summary
A NEW PROTEIN NETWORK IN MUSCLE IS ASSOCIATED WITH MUSCLE DISEASE An intricate protein network connects the contracting mechanism of a muscle to the surrounding cell membrane. Disruption of this connection is one of the known causes of muscular dystrophy. For many patients however the cause of the disease is unknown. We have identified a new region within this protein network that is also associated with muscle disease in mice. A number of proteins that are involved in transmitting chemical mess ....A NEW PROTEIN NETWORK IN MUSCLE IS ASSOCIATED WITH MUSCLE DISEASE An intricate protein network connects the contracting mechanism of a muscle to the surrounding cell membrane. Disruption of this connection is one of the known causes of muscular dystrophy. For many patients however the cause of the disease is unknown. We have identified a new region within this protein network that is also associated with muscle disease in mice. A number of proteins that are involved in transmitting chemical messages from one part of the muscle cell to another are found at this same location. It is possible that disruption of these messages may lead to muscle disease. This project aims to establish the nature of the relationship between the proteins found in this newly identified region of the protein network and muscle diseases such as muscular dystrophy, in both animal models and in humans. We expect that this project may identify new markers for identifying the cause of muscle diseases in some patients and lead to better hopes for an eventual cure.Read moreRead less
DHPR ? Subunit Binding To A Variably Spliced Region Of RyR1: A Role In EC Coupling And Myotonic Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$555,892.00
Summary
We have uncovered a communication pathway between two ion channel molecules in muscle cells that underlies human movement. The pathway is critical in normal mobility and is disrupted in myotonic dystrophy. We will study the molecular components of this pathway to understand normal body function and abnormal function in mytotonic dystrophy. The work will facilitate the design of drugs to relieve the mytotonic dystrophy myopathy and form new and much needed class of specific muscle relaxants.
Novel Features And Mechanisms Of Congenital Myopathies
Funder
National Health and Medical Research Council
Funding Amount
$464,500.00
Summary
Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early childhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In addition, the congen ....Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early childhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In addition, the congenital myopathies have features in common with virtually all muscle diseases such as slow fibre predominance and alterations in contractile force. We are using nemaline myopathy as a representative congenital myopathy to examine features in common amongst the myopathies, characteristic of the congenital myopathies and specific to nemaline myopathy. In nemaline myopathy patients, mutations have been found in five genes that encode proteins of the filamentous systems of the sarcomere. A feature specific to nemaline myopathy is the presence of abnormal structures of the sarcomere called nemaline rods. We have analysed a large number of nemaline myopathy patients that have mutations in the genes that encode the filament proteins alpha-skeletal actin and tropomyosin. In addition, we have generated mouse models for nemaline myopathy and propose to generate an additional one with novel features. Our mouse model has revealed that a feature previously thought exclusive to dystrophies, is also present in nemaline myopathy. The combined analysis of well-characterised patient samples and mouse models will allow us to address longstanding questions about this particular congenital myopathy and myopathies in general. We will determine how rods form and their protein composition. Our mouse models in particular will allow us to address the molecular mechanisms that underpin the increase in slow twitch fibres and the effects that a particular mutation has on muscle function.Read moreRead less
Characterisation Of A Novel Family Of Skeletal Muscle Gene Regulators
Funder
National Health and Medical Research Council
Funding Amount
$443,250.00
Summary
Muscle cells may be broadly divided into two classes, slow- or fast-twitch, with different physiological and biochemical properties. These properties are largely determined by the protein products of several multi-gene families that encode the contractile apparatus characteristic of muscle cells. The pattern of expression of these muscle-specific genes defines a muscle cell as either a slow-twitch or fast-twitch myofibre. Skeletal muscle is inherently plastic in its ability to express different ....Muscle cells may be broadly divided into two classes, slow- or fast-twitch, with different physiological and biochemical properties. These properties are largely determined by the protein products of several multi-gene families that encode the contractile apparatus characteristic of muscle cells. The pattern of expression of these muscle-specific genes defines a muscle cell as either a slow-twitch or fast-twitch myofibre. Skeletal muscle is inherently plastic in its ability to express different genes in response to altered functional demand, and under certain circumstances, fibres can convert from one type to another. Conditions known to cause myofibre conversion in humans include congenital myopathies, spinal injury, and exercise. We have identified a novel family of proteins that regulate the genes that confer fibre type. In this proposal, we will further characterise the function of each of these proteins in skeletal muscle development and fibre determination. In addition, the gene that encodes these proteins is one of many deleted in the human condition Williams-Beuren Syndrome (WBS). WBS is characterised by supravalvular aortic stenosis (SVAS), neurological and cognitive defects, infantile hypercalcemia, dental malformations, musculoskeletal anomalies and growth retardation with short stature. The musculoskeletal anomalies, including joint contractures, muscular pain and kyphoscoliosis, cause WS patients to lack stamina and fatigue easily. An underlying myopathy has been reported and may account for the physical limitations, however the disease causing gene-genes have not been identified. We predict that a lack of the MusTRD proteins contributes to these conditions. In general, the findings from our study will yield insights that will lead to improved treatments of patients who suffer from muscle disease or have sustained a nerve injury and improved approaches to excercise training.Read moreRead less
THE ROLES OF CYTOSKELETAL PROTEINS IN SKELETAL MUSCLE FUNCTION AND DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$466,650.00
Summary
Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early chilhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In nemaline myopathy pat ....Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early chilhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In nemaline myopathy patients, mutations have been found in five genes that encode proteins of the filamentous systems of the sarcomere. Therefore, the genes for other thin filament, thick filament and Z-line proteins are excellent candidates for these disorders. Research from our lab has identified a novel region of the sarcomere and the genes encoding the proteins present in this region provide additional candidates for the congenital myopathies. We will further characterise the proteins in this novel structure to determine its function and the role that it plays in muscle disease pathologies. In order to study the relationship between disease pathology and muscle weakness in nemaline myopathy, we generated a mouse model by expressing a mutant protein, a-tropomyosin slow, found in human patients in mice. All features of the disease found in humans are present in the mice. A key feature of this disease in mice is the ability for muscle cells to grow in diameter or hypertrophy to offset the muscle weakness. We will use these mice to trial therapies including hypertropy-inducing agents, to prevent and reverse muscle weakness. In addition, we will generate an additional mouse model for this disease with a mutation in a gene encoding another filamentous protein. A comparison of the two models using microarray analysis will help us identify additional genes that are being affected in this disease and to generate a molecular expression profile that will aid in the diagnosis of this disease.Read moreRead less