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
Clarifying Molecular Role Of IGF-1:Ea Isoforms In Skeletal Muscle Hypertrophy And Atrophy
Funder
National Health and Medical Research Council
Funding Amount
$394,718.00
Summary
The growth factor IGF-1 is proposed as a therapeutic agent to increase muscle mass and to reduce muscle wasting resulting from denervation, disuse, ageing and dystrophy. Understanding the precise mechanisms of IGF-1 action is essential for the potential therapeutic use of this factor. This research is focused on the molecular role of IGF-1 in healthy muscle and in the conditions of muscle wasting and degeneration.
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.
Targeting Calcineurin For Improving Muscle Regeneration In Skeletal Muscle Disease
Funder
National Health and Medical Research Council
Funding Amount
$303,000.00
Summary
Muscular dystrophy is a term that covers a diverse group of inherited disorders characterised by progressive muscle weakness and wasting. Duchenne muscular dystrophy (DMD) is the most severe form, caused by a lack of a protein called dystrophin, which renders muscles fragile, susceptible to damage, and with a compromised ability to regenerate or repair after injury. The disease progresses to all muscles and DMD patients are dependent on a wheelchair before their early teens and die in their twen ....Muscular dystrophy is a term that covers a diverse group of inherited disorders characterised by progressive muscle weakness and wasting. Duchenne muscular dystrophy (DMD) is the most severe form, caused by a lack of a protein called dystrophin, which renders muscles fragile, susceptible to damage, and with a compromised ability to regenerate or repair after injury. The disease progresses to all muscles and DMD patients are dependent on a wheelchair before their early teens and die in their twenties. There is a profound need for treatments that can ameliorate the dystrophic condition and improve patient quality of life. Restoring or increasing a muscle's capacity to regenerate would help improve muscle function. We have convincing evidence that the calcineurin signal transduction pathway is important for successful muscle regeneration in mice with muscular dystrophy. There is growing excitement worldwide that stimulating calcineurin could attenuate the dystrophic pathology, however, little is known about the role of calcineurin signalling in human muscle disease. Our goals are to investigate the role of calcineurin signalling in muscular dystrophy and to examine its therapeutic potential for enhancing muscle regeneration. Our aim is to better understand the mechanisms controlling calcineurin signalling in muscles of dystrophic mice and in muscles of patients with DMD. A comprehensive series of physiological, molecular, biochemical, and immunohistochemical experiments will be performed to rigorously test our research aim. Understanding the role of the calcineurin pathway in muscle regeneration is important for the development of novel therapeutic strategies to delay the onset or slow the progression of muscle wasting and weakness. The findings will have broad clinical application for our understanding of muscular dystrophy with relevance to other conditions including ageing, AIDS, burns, cancer cachexia, and disuse atrophy, where muscle wasting occurs.Read moreRead less
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