Ketone Bodies Attenuate Wasting in Models of Atrophy
Ketone Bodies Attenuate Wasting in Models of Atrophy
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DOI：
10.1002/jcsm.12554
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发表时间：
2020-04-02
影响因子：
8.9
通讯作者：
D'Agostino, Dominic P.
中科院分区：
文献类型：
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作者：
Koutnik, Andrew P.;Poff, Angela M.;D'Agostino, Dominic P.
癌症厌食恶病质综合征（CACS）是一种独特的萎缩性疾病，对临床护理和患者生活质量的多个方面产生负面影响。虽然它直接导致20%的癌症相关死亡，但目前还没有涵盖整个多方面综合征的模型系统，也没有任何有效的治疗治疗方法。（转移，骨骼肌和脂肪组织消耗，炎症，厌食，贫血，蛋白质分解升高，低白蛋白血症，和代谢紊乱）。离体骨骼肌分析用于确定泛素蛋白酶体降解途径活化。一种新的酮二酯（R/S 1，3-丁二醇乙酰乙酸酯二酯）进行了评估，在多方面的分解代谢环境，以确定抗萎缩efficacy.Results在这里，我们表明，VM-M3小鼠模型的全身转移表现出一种新的，免疫活性，后勤可行，可重复的表型与渐进性肿瘤生长，自发转移扩散，和全多方面的CACS与性别二态性跨组织浪费。我们还证明，泛素蛋白酶体降解途径显著上调与减少胰岛素样生长因子-1/胰岛素和增加FOXO 3a激活，但不是肿瘤坏死因子-α诱导的核因子-κ B激活，驱动骨骼肌萎缩。此外，我们表明，R/S 1，3-丁二醇乙酰乙酸酯管理转移全身代谢，衰减肿瘤负荷指数，减少萎缩/catalytic和减轻共病症状在CACS和癌症无关的atrophic environment.Conclusions我们的研究结果表明，酮二酯衰减多因素CACS骨骼肌萎缩和炎症诱导catalytic，证明抗分解代谢作用的酮体在多因素萎缩。
Background Cancer Anorexia Cachexia Syndrome (CACS) is a distinct atrophy disease negatively influencing multiple aspects of clinical care and patient quality of life. Although it directly causes 20% of all cancer-related deaths, there are currently no model systems that encompass the entire multifaceted syndrome, nor are there any effective therapeutic treatments.Methods A novel model of systemic metastasis was evaluated for the comprehensive CACS (metastasis, skeletal muscle and adipose tissue wasting, inflammation, anorexia, anemia, elevated protein breakdown, hypoalbuminemia, and metabolic derangement) in both males and females. Ex vivo skeletal muscle analysis was utilized to determine ubiquitin proteasome degradation pathway activation. A novel ketone diester (R/S 1,3-Butanediol Acetoacetate Diester) was assessed in multifaceted catabolic environments to determine anti-atrophy efficacy.Results Here, we show that the VM-M3 mouse model of systemic metastasis demonstrates a novel, immunocompetent, logistically feasible, repeatable phenotype with progressive tumor growth, spontaneous metastatic spread, and the full multifaceted CACS with sex dimorphisms across tissue wasting. We also demonstrate that the ubiquitin proteasome degradation pathway was significantly upregulated in association with reduced insulin-like growth factor-1/insulin and increased FOXO3a activation, but not tumor necrosis factor-alpha-induced nuclear factor-kappa B activation, driving skeletal muscle atrophy. Additionally, we show that R/S 1,3-Butanediol Acetoacetate Diester administration shifted systemic metabolism, attenuated tumor burden indices, reduced atrophy/catabolism and mitigated comorbid symptoms in both CACS and cancer-independent atrophy environments.Conclusions Our findings suggest the ketone diester attenuates multifactorial CACS skeletal muscle atrophy and inflammation-induced catabolism, demonstrating anti-catabolic effects of ketone bodies in multifactorial atrophy.