Understanding how amino acid handling influences protein synthesis: a new paradigm in back pain research

BBSRC：Andra-Maria Ionescu：BB/M011208/1背痛长期以来一直被认为是世界各国（包括英国和加拿大）“残疾生活年数”的最重要原因。椎间盘退变（IVD）是背痛的主要原因。健康的IVD是一种位于脊柱椎骨之间的柔软水合组织，它允许灵活性并保护脊柱在负荷期间免受损伤。组织富含蛋白质，细胞相对较少。随着退行性变，细胞功能发生变化，导致组织发生变化，包括水合作用和椎间盘高度的丧失，最终导致背痛。尽管问题的复杂性，但没有长期成功的治疗方法，因此需要新的合作研究领域，以便更好地了解疾病过程并开发新的治疗方法。该项目将允许形成新的合作，以调查IVD研究的一个重要的未研究领域;细胞处理氨基酸的方式是否可能导致疾病，以及氨基酸处理的“拯救”是否可能作为IVD变性和背痛的治疗方法。为了启动这一领域的研究，目前的项目将研究骨骼肌中的氨基酸处理，骨骼肌是一种更好地理解氨基酸处理机制的组织。氨基酸是蛋白质的主要“构建块”，在维持骨骼肌质量方面发挥着重要作用。其中，必需氨基酸亮氨酸特别负责激活新的肌肉蛋白质的产生。因此，认为亮氨酸转运到骨骼肌中可能是激活肌肉蛋白质获得的关键作用，因此，这些对于维持骨骼肌质量和功能以及衰老和疾病是必不可少的。亮氨酸转运主要由两种转运蛋白协调，称为LAT 1（L型氨基酸转运蛋白1）和SNAT 2（钠偶联中性氨基酸转运蛋白2）;然而，这些转运蛋白对骨骼肌大小和蛋白质产生的全部重要性尚不清楚。除了亮氨酸，其他氨基酸，如精氨酸，甘氨酸和甲硫氨酸也被认为能激活增加肌肉蛋白质产量的过程。因此，如果亮氨酸转运受损，或亮氨酸可用性低，这些氨基酸可能对肌肉蛋白质产生和细胞大小具有补偿作用。因此，该项目的目的将是确定抑制亮氨酸转运蛋白LAT 1和SNAT 2如何影响肌肉细胞中的亮氨酸转运、细胞大小和蛋白质产生。此外，我们的目标是了解大量的甘氨酸，精氨酸和/或甲硫氨酸是否可以挽救LAT 1/SNAT 2抑制的任何破坏性作用。这项研究的结果将提供关于骨骼肌细胞中亮氨酸转运和蛋白质产生是如何控制的重要信息。它还将建议在缺乏亮氨酸或亮氨酸运输减少的情况下使用什么营养策略来提高肌肉蛋白质的生产。从研究中获得的知识也将从加拿大翻译到英国，以启动一个新的国际合作研究领域，研究IVD中的氨基酸处理，这有可能最终彻底改变背痛的治疗，从而减轻疾病对两国的相关影响。

BBSRC : Andra-Maria Ionescu : BB/M011208/1Back 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.