Understanding how amino acid handling influences protein synthesis: a new paradigm in back pain research
Lead Research Organisation:
University of Manchester
Department Name: School of Biological Sciences
Abstract
BBSRC : Andra-Maria Ionescu : BB/M011208/1
Back pain has long been recognised as the most significant cause of 'years lived with disability' in countries around the world, including in both the UK and Canada. Degeneration of the intervertebral disc (IVD) is the leading cause of back pain. The healthy IVD a soft, hydrated tissue located between the vertebrae in the spine which allows flexibility and protects the spine from damage during loading. The tissue is protein-rich, with relatively few cells. With degeneration the function of the cells changes, leading to a change in the tissue including a loss of hydration and disc height that ultimately causes back pain. Despite the enormity of the problem there are no long-term successful treatments and hence new areas of collaborative research are required in order to better understand the disease processes and develop novel therapies. This project will allow a new collaboration to be formed in order to investigate an important unstudied area of IVD research; whether they way in which cells handle amino acids might cause disease and whether 'rescue' of amino acid handling might have potential as a treatment for IVD degeneration and back pain. To initiate this area of research the current project will investigate amino acid handling in skeletal muscle, a tissue in which the mechanisms of amino acid handling are better understood.
Amino acids are the main 'building blocks' of proteins and have an important role in the maintenance of skeletal muscle mass. Of these, the essential amino acid leucine, is particularly responsible for the activation of new muscle protein production. Therefore, it is thought that the transport of leucine into skeletal muscle may be pivotal role in the activation of muscle protein gain and thus, these could be essential for maintaining skeletal muscle mass and function with ageing and disease. Leucine transport is coordinated predominantly by two transporters, called LAT1 (L-Type Amino Acid Transporter 1) and SNAT2 (sodium-coupled neutral amino acid transporter 2); however the full importance of these transporters to skeletal muscle size and protein production is unknown. As well as leucine, other amino acids, such as arginine, glycine and methionine are also believed to activate the processes which increase muscle protein production. Therefore, if leucine transport is impaired, or leucine availability is low, these amino acids may have a compensatory effect on muscle protein production and cell size.
Thus, the aim of this project will be to determine how inhibiting the leucine transporters LAT1 and SNAT2 affects leucine transport, cell size and protein production in muscle cells. Furthermore, we will then aim to understand whether high amounts of glycine, arginine and/or methionine can rescue any damaging effects of LAT1/SNAT2 inhibition.
The results of this investigation will provide vital information on how leucine transport and protein production are controlled in skeletal muscle cells. It would also advise on what nutritional strategies to use to enhance muscle protein production in cases where there is a lack of leucine or reduced leucine transport.
The knowledge gained from the study will also then be translated across from Canada to the UK to initiate a new area of collaborative international research into study of amino acid handling in the IVD which has the potential ultimately to revolutionise treatment of back pain and thereby alleviate the associated impact of the disease to both countries.
Back pain has long been recognised as the most significant cause of 'years lived with disability' in countries around the world, including in both the UK and Canada. Degeneration of the intervertebral disc (IVD) is the leading cause of back pain. The healthy IVD a soft, hydrated tissue located between the vertebrae in the spine which allows flexibility and protects the spine from damage during loading. The tissue is protein-rich, with relatively few cells. With degeneration the function of the cells changes, leading to a change in the tissue including a loss of hydration and disc height that ultimately causes back pain. Despite the enormity of the problem there are no long-term successful treatments and hence new areas of collaborative research are required in order to better understand the disease processes and develop novel therapies. This project will allow a new collaboration to be formed in order to investigate an important unstudied area of IVD research; whether they way in which cells handle amino acids might cause disease and whether 'rescue' of amino acid handling might have potential as a treatment for IVD degeneration and back pain. To initiate this area of research the current project will investigate amino acid handling in skeletal muscle, a tissue in which the mechanisms of amino acid handling are better understood.
Amino acids are the main 'building blocks' of proteins and have an important role in the maintenance of skeletal muscle mass. Of these, the essential amino acid leucine, is particularly responsible for the activation of new muscle protein production. Therefore, it is thought that the transport of leucine into skeletal muscle may be pivotal role in the activation of muscle protein gain and thus, these could be essential for maintaining skeletal muscle mass and function with ageing and disease. Leucine transport is coordinated predominantly by two transporters, called LAT1 (L-Type Amino Acid Transporter 1) and SNAT2 (sodium-coupled neutral amino acid transporter 2); however the full importance of these transporters to skeletal muscle size and protein production is unknown. As well as leucine, other amino acids, such as arginine, glycine and methionine are also believed to activate the processes which increase muscle protein production. Therefore, if leucine transport is impaired, or leucine availability is low, these amino acids may have a compensatory effect on muscle protein production and cell size.
Thus, the aim of this project will be to determine how inhibiting the leucine transporters LAT1 and SNAT2 affects leucine transport, cell size and protein production in muscle cells. Furthermore, we will then aim to understand whether high amounts of glycine, arginine and/or methionine can rescue any damaging effects of LAT1/SNAT2 inhibition.
The results of this investigation will provide vital information on how leucine transport and protein production are controlled in skeletal muscle cells. It would also advise on what nutritional strategies to use to enhance muscle protein production in cases where there is a lack of leucine or reduced leucine transport.
The knowledge gained from the study will also then be translated across from Canada to the UK to initiate a new area of collaborative international research into study of amino acid handling in the IVD which has the potential ultimately to revolutionise treatment of back pain and thereby alleviate the associated impact of the disease to both countries.
