Novel targets for increased muscle growth or feed efficiency

An increase in the global demand for food is predicted between now and 2050. Without major advances in food production, food shortages will become more frequent across the globe, including developed parts of the world. It is therefore essential that we ensure sufficient food is available to establish "global food security". The world population currently stands at 7 billion but is predicted to increase to 9 billion by 2050. This is a major threat to food security, but there are also other exacerbating pressures. There is a need to reduce greenhouse gas emissions to reduce global warming and climate change, while land and crops are being increasingly used to produce alternative energy sources to fossil fuels (coal, gas and oil). This leads to competition for land, water, energy and the sources of food themselves. To produce more food requires either more land (which isn't available) or an improvement in the efficiency of production. Increases in personal wealth in developing countries is predicted to increase the demand for meat and animal products, which consumers associate with a higher quality diet and social status. However, meat requires significantly more resource to produce than other foods. Meat producing animals, such as pigs and poultry, commonly require grain-based feeds which will become an increasingly limited resource, due to competition from human diets and the biofuels industry. These pressures make it important to reduce the quantity of feed required per unit meat (or other product) produced, thereby improving "feed efficiency". To do this, use of technologies will be required including those not currently deemed acceptable to the consumer (in the EU at least), although threats to food security may change consumers values and ethical stances.
For efficient production of meat, the goal is to maximize the deposition of nutrients (particularly protein) into skeletal muscle and repartition nutrients (particularly those for energy) away from fat. Animal growth promoters are used legally in some countries (Australia, Brazil and USA), but not the EU, and have the effect of increasing lean tissue mass while decreasing body fat. Our aim is to identify novel genes that more specifically target an anabolic and/or energy-sparing mechanism and are more efficacious and greener/safer than the currently available classes of compounds. Recent work at Nottingham combining animal studies with systems biology analyses of genes in muscle, liver and adipose tissue and blood metabolites has identified a number of novel genes whose expression is associated with increased muscle growth. Importantly, this work is ongoing and therefore will continue to identify potential target genes to 2015. The objective of this project is therefore to verify whether these novel target genes really can improve muscle growth and/or feed efficiency. This will be done initially in muscle cell culture studies, whereby the individual target genes will be increased or decreased and the effect on muscle cell growth determined. This work will be done initially using the mouse C2C12 muscle cell line, then primary pig satellite cells. A selection of targets from this muscle cell culture work will then be studied in mice, whereby expression of the target gene will again be increased or decreased in muscle or the target protein or a related drug will be injected and muscle growth monitored non-invasively over time by repeated CT scanning and feed efficiency measured using metabolic cages. The expectation is that specific genes will be identified which enhance the efficiency of muscle growth and which could therefore be targets for drugs to be developed in the future that will increase muscle growth and improve feed efficiency.

Global Food Security is becoming an increasingly important issue and strategies to improve animal feed efficiency are urgently needed. We are investigating the changes in muscle, liver and adipose tissue transcriptomes and blood metabolome in response to known anabolic agents, growth hormone and beta-agonist, over a 27 day time course in pigs. These studies will continue until 2015, but have already identified a number of genes not previously associated with muscle growth. We also have strong links with Zoetis and a group in China investigating genetic markers of improved feed efficiency in pigs, which is also identifying novel genes, many associated with muscle metabolism. We now need to evaluate these genes further to establish whether they really do increase muscle growth and/or feed efficiency. This will be done by manipulating their expression (via overexpression or siRNA) or availability/activity (via proteins, compounds or antibodies) in cultured muscle cells and determining the effects on muscle cell proliferation, differentiation, metabolism and myotube size. These studies will be done using the mouse-derived C2C12 muscle cell line and primary pig satellite cells. A subset of these genes will then be further studied in mice, either using compounds/ biopharmaceuticals to manipulate the target genes (so-called systemic or non-muscle targets) or by injection of AAV constructs directly into muscle. The effects on muscle growth will be determined by repeated CT scanning (all targets) over a 28d period; while effects on feed efficiency will be determined using the CLAMS metabolic cage system (systemic targets only). Changes in molecular and physical characteristics of muscle (and other relevant tissues) will be determined over the time-course. The expectation is that specific genes will be identified which enhance the efficiency of muscle growth and which could therefore be targets for drugs to be developed in the future.

The overall aim is to identify novel genes that may be drug targets to increase muscle growth and feed efficiency in pigs (and possibly other livestock), which will obviously benefit our Industrial partner, Zoetis, in their search for new drugs. However, Zoetis will not be the only beneficiaries. From an academic point of view, the work will dramatically enhance our understanding of how muscle growth and metabolism are regulated at the molecular level. Importantly, this information may then be developed into a better understanding of other species, including man. Indeed, much of the early basic research on the use of growth promoters in farm animals has subsequently been translated into humans for the treatment of muscle-related diseases such as muscular dystrophies and sarcopenia. We therefore believe the work proposed will also eventually be translatable into benefits for human medicine.
The ultimate impact will be in the form of a drug that improves the efficiency of meat production, thereby contributing to the protection of food security worldwide. By making animal production systems more efficient, there will obviously be impacts on the farmers/producers, but also on the general public via improvements in food security (availability and/or cost of meat and meat products).