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.

项目摘要 肥胖是退伍军人社区和全国各地流行比例的临床问题。这是不利的 影响几乎每个器官，并引起代谢功能障碍，包括慢性炎症，胰岛素抵抗 和糖尿病，血脂异常和心血管疾病。肥胖的并发症不足的是 导致肌肉萎缩。这浪费导致肌肉无力和脆弱，这增加了事件的事件 瀑布，降低生活质量，并与更高的合并症和风险相关 死亡。动物和患者的证据表明，肥胖可以通过 损害肌发生（即纤维修复），并通过衰减蛋白质合成和加速蛋白水解。 先前的研究记录了多种蛋白水解系统的激活 - 泛素 - 蛋白酶体，， 自噬和caspase -3系统 - 在肥胖数据库/dB小鼠中，我们的实验室指标最近的研究 可以通过将培养的C2C12肌管与棕榈酸酯一起孵育，这是人体最多的一种，可以复制反应 丰富的饱和脂肪酸。棕榈酸酯加速了C2C12肌管中蛋白质降解的速率 减少胰岛素信号传导并刺激肥胖中上调的所有三个蛋白水解系统 老鼠。我们最近通过证明棕榈酸酯诱导的ER应力来扩展这些发现 有助于产生与萎缩相关的基因和蛋白质表达。 Myostatin（MSTN），成员 BMP/TGFß超家族有助于诱导萎缩相关的蛋白水解蛋白质降解 肥胖患者和动物的肌肉中酶和肌动物的增加。新的初步数据 证明棕榈酸酯会诱导MSTN mRNA。基于这些发现，我们建议调查是否 肥胖通过激活C/EBP和 CREB转录因子通过两种与ER应力和Akt-相关的新鉴定的信号传导机制 分别调节的磷酸二酯酶（PDE3/4）（AIM 1）。 MSTN增加了萎缩的表达 相关蛋白质部分是通过AKT损害胰岛素和IGF-1信号传导，从而激活分解代谢 但是，FOXO转录因子），但是，MSTN如何减少AKT活性仍然未知。在AIM 2中，我们将 研究MSTN相关的microRNA-29的抑制以及其目标之一的表达增加 - 磷酸酶和Tensin同源物（PTEN）有助于AKT失调，并增加了FOXO介导的 骨骼肌和肌管中的基因表达。在AIM 3中，我们将测试饮食中是否提供Omega-3 多不饱和脂肪酸（N-3 PUFA）到DB/DB小鼠逆转与肥胖相关功能失调的MSTN信号传导 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 施用N-3 PUFA可以在癌症，肾衰竭和 其他与萎缩相关的疾病。我们的初步数据表明，N-3 PUFA，docosahexaenoic 酸（DHA）防止棕榈酸酯诱导的MSTN表达变化以及Akt-Foxo和ER应激 与肌肉胸前表达相关的信号传导。我们建议实现这些有益的效果 通过逆转肥胖相关的功能失调的信号传导，产生MSTN和其他蛋白质分解代谢反应 最终导致肌肉萎缩。 AIM 3的结果将提供新的临床前证据以支持 将N-3 PUFA用作具有成本效益的疗法来抵抗肥胖对的不利影响的可行性 退伍军人的骨骼肌质量。