Mechanisms of obesity-linked muscle atrophy and n-3 fatty acids

肥胖相关肌肉萎缩的机制和 n-3 脂肪酸

• 批准号: 9350140
• 负责人: S. Russ Price
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9350140
• 关键词: Adverse effects; Affect; Alpha Cell; Animals; Atrophic; Attenuated; Autophagocytosis; CASP3 gene; CCAAT-Enhancer-Binding Proteins; CREB1 gene; Cardiovascular Diseases; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chronic; Clinical; Clinical Practice Guideline; Communities; Comorbidity; Complication; Country; Data; Diabetes Mellitus; Diet; Docosahexaenoic Acids; Dyslipidemias; Eicosapentaenoic Acid; Elderly; Enzymes; Epidemic; FOXO1A gene; Fiber; Functional disorder; GDF8 gene; Gene Expression; Genes; Glucocorticoids; Goals; Impairment; In Vitro; Incidence; Incubated; Inflammation; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Kidney Failure; Lead; Link; MADH2 gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical center; Messenger RNA; Metabolic; MicroRNAs; Mind; Modeling; Muscle; Muscle Cells; Muscle Fibers; Muscle Proteins; Muscle Weakness; Muscle function; Muscular Atrophy; N-3 polyunsaturated fatty acid; Non obese; Obese Mice; Obesity; Omega-3 Fatty Acids; Organ; Overweight; PTEN gene; Palmitates; Pathway interactions; Patients; Peptide Hydrolases; Polyunsaturated Fatty Acids; Process; Production; Protein Biosynthesis; Proteins; Proteolysis; Quality of life; Reporting; Risk; Saturated Fatty Acids; Signal Transduction; Signaling Protein; Skeletal Muscle; Stress; System; Testing; Transcription Factor 3; Transforming Growth Factor beta; Ubiquitin; Veterans; animal data; base; biological adaptation to stress; cost; cost effective; db/db mouse; effective therapy; experimental study; falls; frailty; improved; in vivo; insulin signaling; lean body mass; member; mortality; multicatalytic endopeptidase complex; muscle form; myogenesis; phosphoric diester hydrolase; pre-clinical; prevent; protective effect; protein degradation; protein expression; receptor; repaired; response; sarcopenic obesity; screening; transcription factor; wasting

PROJECT SUMMARY Obesity is a clinical issue of epidemic proportion in the Veteran community and across the country. It adversely affects almost every organ and causes metabolic dysfunction including chronic inflammation, insulin resistance and diabetes, dyslipidemias, and cardiovascular disease. An underappreciated complication of obesity is that it causes muscle atrophy. This wasting leads to muscle weakness and frailty which increases the incidence of falls, reduces the quality of life, and is associated with a higher incidence of co-morbidities and risks of mortality. Evidence from animals and patients indicates that obesity decreases muscle size and strength by impairing myogenesis (i.e., fiber repair) and by attenuating protein synthesis and accelerating proteolysis. Previous studies have documented activation of multiple proteolytic systems - the ubiquitin-proteasome, autophagy and caspase-3 systems - in obese db/db mice and recent studies by our lab indicate that these responses can be duplicated by incubating cultured C2C12 myotubes with palmitate, one of the body’s most abundant saturated fatty acids. Palmitate accelerates the rate of protein degradation in C2C12 myotubes by reducing insulin signaling and stimulating all three of the proteolytic systems that are up-regulated in obese mice. We have extended these findings by recently demonstrating that palmitate-induced ER stress also contributes to the production of atrophy-related gene and protein expression. Myostatin (MSTN), a member of the BMP/TGFß superfamily, contributes to protein degradation by inducing atrophy-related proteolytic enzymes and the myokine is increased in muscle of obese patients and animals. New preliminary data demonstrate that palmitate induces MSTN mRNA. Based on these findings, we propose to investigate whether obesity contributes to MSTN expression in myotubes and skeletal muscle in vivo by activating the C/EBP and CREB transcription factors via two newly identified signaling mechanisms linked to ER stress and Akt- regulated phosphodiesterases (PDE3/4), respectively (Aim 1). MSTN increases the expression of atrophy- related proteins, in part, by impairing insulin and IGF-1 signaling through Akt, which activates the catabolic FoXO transcription factors), however, it remains unknown how MSTN reduces Akt activity. In Aim 2, we will investigate whether MSTN-related suppression of microRNA-29 and increased expression of one of its targets - phosphatase and tensin homolog (PTEN) contributes to Akt dysregulation and increased FoxO-mediated gene expression in skeletal muscle and myotubes. In Aim 3, we will test whether dietary provision of omega-3 polyunsaturated fatty acids (n-3 PUFA) to db/db mice reverses obesity-related dysfunctional MSTN signaling and protein catabolic responses that lead to muscle atrophy. Recent animal and patient studies provide evidence that administration of n-3 PUFA can produce muscle-sparing effects in cancer, kidney failure and other atrophy-associated conditions. Our preliminary data demonstrate that a n-3 PUFA, docosahexaenoic acid (DHA), prevents the palmitate-induced changes in MSTN expression and Akt-FoxO and ER stress signaling that are linked to muscle atrogene expression. We propose that these beneficial effects are achieved by reversing obesity-related dysfunctional signaling that produce MSTN and other protein catabolic responses which ultimately lead to muscle atrophy. Results from Aim 3 will provide new preclinical evidence to support the feasibility of using of n-3 PUFA as a cost-effective therapy to counter the adverse effects of obesity on skeletal muscle mass in Veterans.

项目总结 在退伍军人社区和全国范围内，肥胖是一个临床流行比例问题。它带来了负面影响 几乎影响到每个器官，并导致代谢功能障碍，包括慢性炎症、胰岛素抵抗 糖尿病、血脂异常和心血管疾病。肥胖症一个被低估的并发症是它 会导致肌肉萎缩。这种消瘦导致肌肉无力和虚弱，从而增加了 跌倒，降低生活质量，并与更高的合并症发生率和 死亡率。来自动物和患者的证据表明，肥胖通过以下方式减少肌肉大小和力量 损害肌肉生成(即纤维修复)，并通过减弱蛋白质合成和加速蛋白质分解来实现。 以前的研究已经证明了多种蛋白分解系统的激活-泛素-蛋白酶体， 肥胖db/db小鼠的自噬和caspase-3系统，以及我们实验室最近的研究表明，这些系统 通过将培养的C2C12肌管与棕榈酸酯孵育可以复制反应，棕榈酸酯是人体最重要的 丰富的饱和脂肪酸。棕榈酸酯通过以下途径加速C2C12肌管蛋白质降解 减少胰岛素信号并刺激肥胖症患者上调的所有三种蛋白分解系统 老鼠。我们扩展了这些发现，最近证明了棕榈酸酯诱导的内质网应激也 有助于产生与萎缩相关的基因和蛋白表达。肌肉生长抑素(MSTN)，成员 骨形态发生蛋白/转化生长因子超家族通过诱导萎缩相关蛋白降解促进蛋白质降解 肥胖症患者和动物肌肉中的酶和肌动蛋白增加。新的初步数据 证明棕榈酸酯可诱导MSTN基因的表达。基于这些发现，我们建议调查 肥胖通过激活C/EBP和MSTN促进肌管和骨骼肌MSTN的表达 CREB转录因子通过两个新发现的信号机制与内质网应激和Akt- 调节磷酸二酯酶(PDE3/4)(目标1)。MSTN增加萎缩的表达- 相关蛋白，部分是通过Akt损害胰岛素和IGF-1信号，从而激活分解代谢 FOXO转录因子)，然而，MSTN如何降低Akt活性仍不清楚。在目标2中，我们将 研究MSTN是否与microRNA-29的抑制和其靶标之一的表达增加有关 -磷酸酶和紧张素同源物(PTEN)导致Akt失调和FoxO介导的增加 基因在骨骼肌和肌管中的表达。在目标3中，我们将测试膳食中是否提供omega-3 Db/db小鼠多不饱和脂肪酸(n-3PUFA)逆转肥胖相关的MSTN信号转导 以及导致肌肉萎缩的蛋白质分解代谢反应。最近的动物和患者研究提供了 有证据表明，服用n-3多不饱和脂肪酸可以在癌症、肾功能衰竭和 其他与萎缩相关的疾病。我们的初步数据表明，n-3多不饱和脂肪酸，二十二碳六烯酸 酸(DHA)，阻止棕榈酸酯诱导的MSTN表达和Akt-FoxO和ER应激的变化 与肌肉萎缩性基因表达相关的信号。我们认为，这些有益的效果是实现的 通过逆转产生MSTN和其他蛋白质分解代谢反应的肥胖相关功能障碍信号 最终导致肌肉萎缩。AIM 3的结果将提供新的临床前证据支持 N-3多不饱和脂肪酸作为一种经济有效的治疗方法对抗肥胖的不良影响的可行性 退伍军人的骨骼肌群。