BackgroundCancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and ongoing skeletal muscle loss resulting in weakness, poor quality of life, and decreased survival. Whereas lipid accumulation in skeletal muscle is associated with cancer cachexia as well as the prognosis of cancer patients, surprisingly little is known about the nature of the lipids that accumulate in the muscle during cachexia, and whether this is related to inflammation. We aimed to identify the types and distributions of intramyocellular lipids in patients with and without cancer cachexia.MethodsRectus abdominis muscle biopsies were collected during surgery of patients with pancreatic ductal adenocarcinoma (n = 10 without cachexia, n = 20 cachectic without inflammation (CRP < 10 mg/L), n = 10 cachectic with inflammation (CRP ≥ 10 mg/L). L3‐CT scans were analysed to assess body composition based on validated thresholds in Hounsfield units (HU). Muscle sections were stained with Oil‐Red O and H&E to assess general lipid accumulation and atrophy. Untargeted lipidomic analyses were performed on laser‐microdissected myotubes using LC–MS/MS. The spatial distribution of intramyocellular lipids with differential abundance between groups was visualized by mass‐spectrometry imaging. Genes coding for inflammation markers and enzymes involved in de novo ceramide synthesis were studied by qPCR.ResultsMuscle radiation attenuation was lower in cachectic patients with inflammation (median 24.3 [18.6–30.8] HU) as compared with those without inflammation (34.2 [29.3–38.7] HU, P = 0.033) or no cachexia (37.4 [33.9–42.9] HU, P = 0.012). Accordingly, intramyocellular lipid content was lower in non‐cachectic patients (1.9 [1.6–2.1]%) as compared with those with cachexia with inflammation (5.5 [4.5–7.3]%, P = 0.002) or without inflammation (4.8 [2.6–6.0]%, P = 0.017). Intramyocellular lipid accumulation was associated with both local IL‐6 mRNA levels (rs = 0.57, P = 0.015) and systemic CRP levels (rs = 0.49, P = 0.024). Compared with non‐cachectic subjects, cachectic patients had a higher relative abundance of intramyocellular glycerophospholipids and a lower relative abundance of glycerolipids. Furthermore, increases in several intramyocellular lipids such as SM(d36:1), PC(34:1), and TG(48:1) were found in cachectic patients with inflammation and correlated with specific cachexia features. Altered intramyocellular lipid species such as PC(34:1), LPC(18:2), and TG(48:1) showed an uneven distribution in muscle sections of cachectic and non‐cachectic patients, with areas featuring abundance of these lipids next to areas almost devoid of them.ConclusionsIntramyocellular lipid accumulation in patients with cachexia is associated with both local and systemic inflammation, and characterized by changes in defined lipid species such as glycerolipids and glycerophospholipids.

中文翻译：

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人胰腺癌恶病质中炎症相关的肌细胞内脂质变化


背景癌症恶病质是一种多因素代谢综合征，其特征是全身炎症和持续的骨骼肌损失，导致虚弱、生活质量差和生存率下降。尽管骨骼肌中的脂质积累与癌症恶病质以及癌症患者的预后有关，但令人惊讶的是，人们对恶病质期间肌肉中积累的脂质的性质以及这是否与炎症有关知之甚少。我们的目的是确定患有和不患有癌症恶病质的患者肌细胞内脂质的类型和分布。方法在胰腺导管腺癌患者的手术过程中收集腹直肌活检组织（n = 10无恶病质，n = 20恶病质无炎症（CRP < 10） mg/L），n = 10 恶病质伴炎症（CRP ≥ 10 mg/L）进行分析，以根据亨斯菲尔德单位 (HU) 的验证阈值评估身体成分。肌肉切片用油红 O 染色。使用 LC-MS/MS 对激光显微解剖肌管进行非靶向脂质组学分析，通过质谱成像可视化组间丰度差异的肌细胞内脂质的空间分布。通过 qPCR 研究参与神经酰胺从头合成的标记物和酶。结果与无炎症患者 (34.2 [29.3–38.7] HU，P = 0.033）或无恶病质（37.4 [33.9–42.9] HU，P = 0.012）。因此，非恶病质患者的肌细胞内脂质含量较低（1.9 [1.6-2.1]%）与有炎症的恶病质患者（5.5 [4.5–7.3]%，P = 0.002）或无炎症的恶病质患者（4.8 [2.6–6.0]%，P = 0.017）相比。肌细胞内脂质积累与局部 IL-6 mRNA 水平（rs = 0.57，P = 0.015）和全身 CRP 水平（rs = 0.49，P = 0.024）相关。与非恶病质受试者相比，恶病质患者的肌细胞内甘油磷脂相对丰度较高，而甘油脂相对丰度较低。此外，在患有炎症的恶病质患者中发现了几种肌细胞内脂质的增加，例如 SM(d36:1)、PC(34:1) 和 TG(48:1)，并且与特定的恶病质特征相关。改变的肌细胞内脂质种类，如 PC(34:1)、LPC(18:2) 和 TG(48:1) 在恶病质和非恶病质患者的肌肉切片中表现出不均匀分布，接下来是这些脂质丰富的区域结论 恶病质患者的肌细胞内脂质积累与局部和全身炎症相关，其特征是特定脂质种类（例如甘油脂和甘油磷脂）的变化。