The effect of obesity-induced cytokine elevation on the molecular regulation of protein turnover and carbohydrate metabolism in human skeletal muscle

肥胖引起的细胞因子升高对人体骨骼肌蛋白质周转和碳水化合物代谢分子调节的影响

• 批准号: BB/G011435/1
• 负责人: Paul Greenhaff
• 金额: $ 75.34万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG011435%2F1
• 关键词: effect; obesity; induced; cytokine; elevation

Obesity in humans has been shown to result in the increased release of small inflammatory-inducing proteins, called cytokines, from the fat cells of the body. We are interested in the effects of these cytokines on the mechanisms that control muscle mass and metabolism in the obese human. Previous research from work in cells and animals has shown the cytokines reduce the synthesis of muscle proteins and simultaneously enhance their rate of breakdown, resulting in a loss of muscle mass. Furthermore, research suggests that the same cytokines may inhibit carbohydrate oxidation, a pivotal step in muscle metabolism. However, despite these potential negative consequences for skeletal muscle function, the effect of low-level and persistent inflammation as seen in obese humans, remains largely unknown. Our animal based work demonstrated, for the first time, that the molecular events that occur in muscle to reduce muscle mass and inhibit carbohydrate oxidation operate, at least following statin-induced myopathy and sepsis, in unison. Moreover, these events appear to be dependent on the inactivation of a single enzyme, called AKT. Interestingly, the molecular events that result in increased activity of AKT also appear inhibited by the cytokines. Given the findings from cell and animal research, we believe that in obese individuals, where levels of cytokines in the blood are elevated, synthesis of muscle proteins and carbohydrate oxidation may be reduced and breakdown of muscle proteins increased, and that these observations are due to cytokine inactivation of the AKT enzyme. In the current application, we therefore wish to measure the rates of synthesis and breakdown of muscle proteins in conjunction with rates of carbohydrate oxidation in obese individuals, and compare them to rates determined in healthy non-obese individuals. We intend to make these measurements by utilising stable isotope techniques and determining O2 uptake and CO2 production by the subject. Furthermore, we intend to obtain tissue samples from the thigh muscles of volunteers, allowing us to examine the molecular signalling events that underpin these processes and thus determine for the first time the effect of obesity associated low-dose chronic inflammation on essential muscle events. Following these initial determinations, we will start the subjects on a 12-week course of either pioglitazone, an insulin-sensitiser often prescribed to type II diabetics, or a placebo. Pioglitazone and similar compounds have been shown to increase the activity of AKT in obese and diabetic patients and normalise the levels of cytokines in the blood of the former. By repeating the initial measurements described above, and by accurately determining the levels of the cytokines, we hope to elucidate their role in the instigation of any molecular or functional effect in the obese individual. Furthermore, we wish to determine if an insulin sensitising agent can reverse purported effects of obesity on molecular events in muscle and moreover, lead to functional improvements in synthesis and breakdown of muscle proteins and muscle carbohydrate metabolism. The proposed experiments will be performed in the Centre for Integrated Systems Biology and Medicine (CISBM; www.nottingham.ac.uk/cisbm) at the University of Nottingham Medical School, where integrated human physiology is a major research focus. This work is essential because it will further our understanding of the health consequences of obesity which is all the more important given the purported obesity epidemic threatening to face the Western World in future years. Furthermore, this work may have implications for other disease states characterised by low-grade chronic inflammation. This work therefore falls within the strategic plan of the Diet and Health theme of the BBSRC Agri-Foods Committee.

人类的肥胖已被证明会导致体内脂肪细胞释放更多的小的炎症诱导蛋白，称为细胞因子。我们感兴趣的是这些细胞因子对控制肥胖人群肌肉质量和代谢的机制的影响。以前在细胞和动物中的研究表明，细胞因子减少了肌肉蛋白的合成，同时提高了它们的分解速度，导致肌肉质量的损失。此外，研究表明，相同的细胞因子可以抑制碳水化合物氧化，这是肌肉代谢的关键步骤。然而，尽管对骨骼肌功能有这些潜在的负面影响，但在肥胖人群中观察到的低水平和持续性炎症的影响在很大程度上仍然未知。我们基于动物的工作首次证明，至少在他汀类药物诱导的肌病和败血症后，肌肉中发生的减少肌肉质量和抑制碳水化合物氧化的分子事件是一致的。此外，这些事件似乎依赖于一种称为AKT的酶的失活。有趣的是，导致AKT活性增加的分子事件似乎也受到细胞因子的抑制。鉴于细胞和动物研究的结果，我们认为，在肥胖个体中，血液中细胞因子水平升高，肌肉蛋白质的合成和碳水化合物氧化可能减少，肌肉蛋白质的分解增加，这些观察结果是由于AKT酶的细胞因子失活。因此，在本申请中，我们希望测量肥胖个体中肌肉蛋白质的合成和分解速率以及碳水化合物氧化速率，并将它们与健康非肥胖个体中测定的速率进行比较。我们打算通过利用稳定同位素技术和确定O2吸收和CO2生产的主题，使这些测量。此外，我们打算从志愿者的大腿肌肉中获得组织样本，使我们能够检查支持这些过程的分子信号传导事件，从而首次确定肥胖相关的低剂量慢性炎症对基本肌肉事件的影响。在这些初步确定后，我们将开始对受试者进行为期12周的吡格列酮（一种常用于II型糖尿病患者的胰岛素增敏剂）或安慰剂治疗。吡格列酮和类似的化合物已被证明可以增加肥胖和糖尿病患者中AKT的活性，并使前者血液中细胞因子的水平正常化。通过重复上述的初始测量，并通过准确测定细胞因子的水平，我们希望阐明它们在肥胖个体中的任何分子或功能效应中的作用。此外，我们希望确定胰岛素增敏剂是否可以逆转肥胖对肌肉中分子事件的所谓影响，并且还导致肌肉蛋白质合成和分解以及肌肉碳水化合物代谢的功能改善。拟议的实验将在诺丁汉大学医学院的综合系统生物学和医学中心（CISBM; www.nottingham.ac.uk/cisbm）进行，其中综合人类生理学是一个主要的研究重点。这项工作是必不可少的，因为它将进一步了解肥胖的健康后果，这是所有更重要的所谓的肥胖流行病威胁要面对西方世界在未来几年。此外，这项工作可能对以低度慢性炎症为特征的其他疾病状态有影响。因此，这项工作福尔斯属于BBSRC农业食品委员会饮食和健康主题的战略计划范围。

项目成果

Statin myalgia does not reduce muscle strength, mass or protein turnover, but is associated with impaired dynamic muscle function and insulin resistance in older male volunteers

他汀类药物肌痛不会降低肌肉力量、质量或蛋白质周转率，但与老年男性志愿者的动态肌肉功能受损和胰岛素抵抗有关

• 发表时间: 2013
• 作者: Mallinson J

Effects of endotoxaemia on protein metabolism in rat fast-twitch skeletal muscle and myocardium.

内毒素血症对大鼠快肌骨骼肌和心肌蛋白质代谢的影响。

• DOI: 10.1371/journal.pone.0006945
• 发表时间: 2009
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Murton AJ

Mechanisms regulating muscle mass during disuse atrophy and rehabilitation in humans.

人类废用性萎缩和康复期间肌肉质量的调节机制。

• DOI: 10.1152/japplphysiol.00962.2010
• 发表时间: 2011
• 期刊: 1985)
• 作者: Marimuthu K