Energy Use And Work Output By Cross-bridges In Fast- And Slow-twitch Muscles
Funder
National Health and Medical Research Council
Funding Amount
$191,177.00
Summary
All voluntary movement is produced by the action of skeletal muscles. The muscles provide the mechanical power required to move the limbs and the body. To do so, they require energy which is ultimately derived from the breakdown of food. Therefore, we can describe the fundamental process underlying muscular contraction as the conversion of energy from a chemical form into a mechanical form. This project investigates the relationship between the breakdown of molecules that provide energy and the ....All voluntary movement is produced by the action of skeletal muscles. The muscles provide the mechanical power required to move the limbs and the body. To do so, they require energy which is ultimately derived from the breakdown of food. Therefore, we can describe the fundamental process underlying muscular contraction as the conversion of energy from a chemical form into a mechanical form. This project investigates the relationship between the breakdown of molecules that provide energy and the production of mechanical energy or work. Normal contraction involves many cyclic interactions between two proteins, actin and myosin. Each cycle produces a tiny force that contributes to the shortening of the muscle. For over 30 years, it has been thought that energy required for each force producing cycle was provided by the breakdown of one energy-providing molecule, called ATP. Almost all current models of muscle contraction are based on this idea. Recently, data from studies using isolated actin and myosin and observing their interaction in vitro have indicated that many force-producing cycles may be performed with the energy from just one ATP. If this is correct, it will revolutionise our ideas about the way muscles convert chemical energy into mechanical energy. However, the interaction of proteins in a dish is far removed from a normal muscle and the aim of this project is to determine the relationship between force producing cycles and energy use in intact muscles. If multiple force-producing cycles can be powered by one ATP molecule in intact muscle too, then the current idea that the biochemical processes that release energy from ATP are intimately linked to the mechanical changes in myosin that occur as it produces force will be untenable. In short, we will have to rediscover how muscles convert chemical energy into mechanical energy and find out how that energy can be stored from one force-producing cycle to the next.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.
Understanding The Regulation Of HERG Potassium Channel In The Myometrium At The Time Of Labour
Funder
National Health and Medical Research Council
Funding Amount
$597,661.00
Summary
We have shown that a potassium channel known as hERG falls precipitously at the time of term labour and that blocking this channel causes powerful uterine contractions. This grant will determine how the expression of this channel is regulated in the myometrium and whether changes in hERG channels also occur in premature labour.
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
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.
Understanding The Cause Of Muscle Weakness In Nemaline Myopathy (NM) – Moving Towards The Development Of Targeted Treatments
Funder
National Health and Medical Research Council
Funding Amount
$408,768.00
Summary
Congenital myopathy patients have unremitting, life-long muscle weakness that severely affects their quality of life and ability to perform normal daily activities. Currently no effective therapies exist for these conditions, largely due to our limited understanding of the mechanisms leading to muscle weakness. This ECF aims to determine the cause of weakness and test two therapies which have shown promise for other conditions and can be translated into clinical use for myopathies if effective.