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

BBSRC：Andra-Maria Ionescu：BB/M011208/1背部疼痛长期以来一直被认为是世界各国(包括英国和加拿大)“残疾生活多年”的最重要原因。腰椎间盘退行性变(IVD)是导致背部疼痛的主要原因。健康的IVD是一种柔软的水合组织，位于脊柱的椎骨之间，可以保持灵活性，并保护脊柱在负荷过程中免受损害。组织富含蛋白质，细胞相对较少。随着退变，细胞的功能发生变化，导致组织的变化，包括失去水分和椎间盘高度，最终导致背部疼痛。尽管这一问题十分严重，但没有长期成功的治疗方法，因此需要开展新的合作研究领域，以便更好地了解疾病过程并开发新的治疗方法。该项目将允许形成一个新的合作，以调查IVD研究的一个重要的未研究领域；它们是否与细胞处理氨基酸的方式可能导致疾病，以及氨基酸处理的“挽救”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，这是一种更好地了解氨基酸处理机制的组织。氨基酸是蛋白质的主要“构件”，在维持骨骼肌质量方面起着重要作用。其中，必需的氨基酸亮氨酸特别负责激活新的肌肉蛋白质的产生。因此，亮氨酸进入骨骼肌的转运可能在肌肉蛋白合成的激活中起关键作用，因此，这可能是在衰老和疾病中维持骨骼肌质量和功能所必需的。亮氨酸转运主要由两个转运蛋白协调，称为LAT1(L型氨基酸转运蛋白1)和SNAT2(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生产的全部重要性尚不清楚。除了亮氨酸，精氨酸、甘氨酸和蛋氨酸等其他氨基酸也被认为激活了增加肌肉蛋白质生产的过程。因此，如果亮氨酸运输受损，或者亮氨酸利用率低，这些氨基酸可能会对肌肉蛋白质的产生和细胞大小产生补偿作用。因此，该项目的目的将是确定抑制亮氨酸转运蛋白LAT1和SNAT2如何影响亮氨酸转运蛋白的运输、细胞大小和肌肉细胞中的蛋白质生产。此外，我们将致力于了解高剂量的甘氨酸、精氨酸和/或蛋氨酸是否可以挽救LAT1/SNAT2抑制的任何损害效应。这项研究的结果将为骨骼肌细胞如何控制亮氨酸运输和蛋白质生产提供重要信息。它还将就在缺乏亮氨酸或亮氨酸转运减少的情况下使用什么营养策略来提高肌肉蛋白质产量提出建议。从这项研究中获得的知识随后还将从加拿大转移到英国，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，最终有可能彻底改变背痛的治疗方法，从而减轻这种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.