Award details

Role of mRNA localisation and translational control in muscle growth

Reference	BB/K010115/1
Principal Investigator / Supervisor	Professor Simon Hughes
Co-Investigators / Co-Supervisors
Institution	King's College London
Department	Randall Div of Cell and Molecular Biophy
Funding type	Research
Value (£)	290,894
Status	Completed
Type	Research Grant
Start date	01/07/2013
End date	31/12/2016
Duration	42 months

Abstract

Muscle tissue is extraordinarily responsive to physical activity. Muscle grows with high force exercise and shrinks with inactivity. A decrease in muscle mass is due to both increased protein breakdown and reduced of protein synthesis. We have discovered that activity preferentially regulates translation of certain mRNAs located at muscle fibre ends. The fibre end is uniquely built to resist force and is known to be involved in intracellular signalling. Of several mRNAs that localise to fibre ends, we find that some encode proteins that control muscle growth. Although the role(s) of mRNA localisation are unclear, we hypothesise that one is to permit local control of translation, and thereby muscle growth, in response to activity. During a search for molecular mechanisms regulating translation of fibre end-localised mRNAs, we discovered that a eukaryotic Initiation Factor 4E Binding Protein (eIF4EBP), a known repressor of translational initiation on 5'capped mRNA, is controls how activity regulates translation of specific localised mRNAs. Our objectives are, first, to investigate the function of this particular eIF4EBP in genetically manipulated animals to determine its role in normal muscle growth and development. Second, to use biochemistry and high throughput sequencing to elucidate the full set of mRNAs regulated by the eIF4EBP in response to activity and use them to probe both the mechanism(s) of translational control and the control of growth. Third, to discover how activity regulates the eIF4EBP specifically at the muscle fibre end, through genetic, pharmacological and imaging experiments. In addition to increased understanding of mRNA biology, this work will give insight into how physical activity controls muscle growth, with potential long term benefits for lifestyle choices, treatment of ageing-related muscle atrophy, animal husbandry and sports science.

Summary

Skeletal muscle makes up 40% of our body mass and its maintenance is essential for a good quality of life. In various diseases and particularly in older or hospitalised people, muscle wasting is a serious problem. The physical activity of exercise prevents wasting and increases muscle growth. How the body decides what is an appropriate amount of muscle is unknown, but a likely mechanism is feedback from the force of muscle contraction. We want to find out how muscle tissue detects activity and responds by growing. In the past, we have discovered that early muscle develops similarly in fish, mice and people. Such early muscle development generally involves a fixed programme controlled by our genes. Now, we want to study the role of activity in regulating how genes control later muscle growth. For genes to function, their DNA sequence must be 'translated' into an amino acid sequence, thereby forming the proteins that build the body. The cellular machinery that carries out translation uses a copy of the gene DNA, known as messenger RNA (mRNA) as a template for protein synthesis. We have discovered that certain mRNAs are localised to the ends of muscle fibres. The activity of muscle contraction regulates how rapidly proteins are made from these localised mRNAs, thereby controlling muscle growth and function. We have discovered that a protein called BP3L controls translation of some of these mRNAs. So our first aim is determine the role of BP3L in normal muscle growth in response to activity. We will use zebrafish embryos and larvae because they are a) transparent, so that we can study muscle growth in the living animal, b) easy to manipulate genetically, so we can find out which genes control growth, c) small and accessible, so we can easily control activity of the living muscle. These things are more difficult to do in mammals. Our second aim is to discover the full array of mRNAs regulated by BP3L by using a combination of traditional biochemistry and new genomics methods. This will give us the 'big picture' from which we will use our long experience of muscle biology to focus on specific mRNAs controlling muscle growth and function of mRNAs located at fibre ends. Both BP3L and its known targets are located at muscle fibre ends. These ends transmit force to adjacent tissues by means of a complex set of proteins that form attachments to neighbouring cells. Evidence leads us to hypothesise that these attachments are also activity-detectors that initiate the process of growth in response to certain kinds of contractile activity. So our third aim is to understand how muscle activity regulates BP3L and thereby coordinates muscle growth. As in muscle, translation of localised mRNA in nerve cells is regulated by activity during learning and memory. So our findings may have a broader application. Moreover, one possible hypothesis that we will test is that the physical force produced by activity regulates mRNA translation. Elucidating such a mechanism would have importance throughout biology, as cells in plants and animals respond to physical forces that control their growth, for example in skin callousing or the growth of windswept trees. Understanding the force detection and response systems in skeletal muscle is likely to illuminate the role of force in biology and medicine.

Impact Summary

The general population will benefit through improved advice regarding healthy lifestyle choices. It is increasingly apparent that skeletal muscle is a major contributor to healthy metabolic balance. Increased muscle mass is inversely correlated with, and causes, decreased fat mass and obesity. The mechanism by which exercise regulates muscle, is therefore of direct importance to improving lifestyle advice. What kind of exercise and how much of it is necessary for a particular individual to keep healthy? Only deep understanding of the interaction between genes and activity can answer this question. Our work will a) develop a new model in which the fundamental biology can be addressed and b) elucidate a novel mechanism by which activity controls muscle growth. Specific groups of people will also benefit. The prevention of ageing-related muscle weakening and sports science are two potential avenues to societal/commercial exploitation. However, as with lifestyle choices, development of applications will require validation work in mammals/humans which will take 5-10 years. The ageing population will benefit. Loss of muscle mass is a key determinant of incapacity, immobility and physical dependency in the elderly. It also contributes significantly to the chance of falls leading to hospitalization and loss of independent living, with huge social and financial consequences (EU-wide costs: ~ Euro14 billion p.a.). Activity prevents muscle wasting and promotes muscle growth at all life stages. Anything that can be done to prevent a decline will have huge societal and economic benefits. Both biomarkers of muscle growth and potential drug targets may be discovered. The timescale to turn our fundamental insights in the control of muscle growth into practical advice for maintaining muscle mass, or therapeutic interventions is likely to be decades. Genetic diseases like muscular dystrophy, cancer cachexia, chronic kidney disease, AIDS and rheumatoid arthritis all leadto loss of muscle strength, decreasing quality of life. Understanding how activity controls muscle growth is essential to optimize muscle maintenance for patients. By studying the biophysical and biochemical responses to activity and force in muscle cell growth, we aim to elucidate mechanisms applying widely across regenerative medicine. The aquaculture industry will benefit. Commercial impact is likely in aquaculture, where enhancing the efficiency of feed conversion into muscle mass is of major economic importance in this increasingly science-based industry, valued at £500M p.a. in the UK. Understanding the how activity controls muscle growth may permit the industry to select appropriate conditions to maximize growth rate, which may also have a husbandry benefit for the fish. Improving aquaculture production is the best current hope for saving devastated wild fish populations and also a significant economic opportunity. The timescale for influence of our work in this area is likely to be 5-10 years. Tissue engineering with a patient's own cells, for example in reconstructive facial surgery, may benefit from understanding of the effect of activity on muscle growth to make muscle of appropriate size. Serious commercial consideration is being given to the growth of meat for human consumption in vitro. Key to success of such projects will be texture, involving appropriate muscle fibre size. Insight into how activity controls muscle growth may find application in sports science, where improved training regimens and fast recovery from injury are essential. Economic opportunities in this area are likely to increase in future. Our lab also has immediate impact on wider society. The Hughes lab routinely invites groups of local school children to visit KCL and learn about our fish and muscle work. We do school visits for science clubs and to discuss animal experimentation.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	Ageing Research: Lifelong Health and Wellbeing
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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