PDF(Pubmed)
Abstract：
Cancer cachexia is clinically defined by involuntary weight loss >5% in <6 mo, primarily affecting skeletal muscle. Here, we aimed to identify sex differences in the onset of colorectal cancer cachexia with specific consideration to skeletal muscle contractile and metabolic functions. Eight-weeks old BALB/c mice (69 males, 59 females) received subcutaneous C26 allografts or PBS vehicle. Tumors were developed for 10-, 15-, 20-, or 25 days. Muscles and organs were collected, in vivo muscle contractility, protein synthesis rate, mitochondrial function, and protein turnover markers were assessed. One-way ANOVA within sex and trend analysis between sexes were performed, P < 0.05. Gastrocnemius and tibialis anterior (TA) muscles became atrophic in male mice at 25 days, whereas female mice exhibited no significant differences in muscle weights at endpoints despite presenting hallmarks of cancer cachexia (fat loss, hepatosplenomegaly). We observed lowered muscle contractility and protein synthesis concomitantly to muscle mass decay in males, with higher proteolytic markers in muscles of both sexes. mRNA of Opa1 was lower in TA, whereas Bnip3 was higher in gastrocnemius after 25 days in male mice, with no significant effect in female mice. Our data suggest relative protections to skeletal muscle in females compared with males despite other canonical signs of cancer cachexia and increased protein degradation markers; suggesting we should place onus upon nonmuscle tissues during early stages of cancer cachexia in females. We noted potential protective mechanisms relating to skeletal muscle contractile and mitochondrial functions. Our findings underline possible heterogeneity in onset of cancer cachexia between biological sexes, suggesting the need for sex-specific approaches to treat cancer cachexia.NEW & NOTEWORTHY Our study demonstrates biological-sex differences in phenotypic characteristics of cancer cachexia between male and female mice, whereby females display many common characteristics of cachexia (gonadal fat loss and hepatosplenomegaly), protein synthesis markers alterations, and common catabolic markers in skeletal muscle despite relatively preserved muscle mass in early-stage cachexia compared with males. Mechanisms of cancer cachexia appear to differ between sexes. Data suggest need to place onus of early cancer cachexia detection and treatment on nonmuscle tissues in females.
摘要：
背景：癌症恶病质在临床上被定义为在<6个月内非自愿体重减轻>5％，主要影响骨骼肌。这里,我们旨在确定结直肠癌恶病质发病的性别差异,并特别考虑骨骼肌收缩和代谢功能.
方法：8周龄BALB/c小鼠（69只雄性，59名女性)接受皮下C26同种异体移植物或PBS载体。肿瘤发展为10-，15-,20-,或25天。收集肌肉和器官，体内肌肉收缩力，蛋白质合成率，线粒体功能，和蛋白质周转标志物进行了评估。进行了性别内部的单向方差分析和性别之间的趋势分析，p<0.05。
结果：雄性小鼠的腓肠肌和TA肌肉在25天开始萎缩，尽管存在癌症恶病质的标志（脂肪减少，肝脾肿大）。我们观察到男性肌肉收缩性和蛋白质合成降低，伴随着肌肉质量衰减，在男女肌肉中具有较高的蛋白水解标记。在TA中Opa1的mRNA较低，而雄性小鼠25天后腓肠肌中的Bnip3较高，对雌性小鼠无显著影响。
结论：我们的数据表明，与男性相比，女性对骨骼肌的相对保护，尽管有其他癌症恶病质的典型迹象和蛋白质降解标志物增加；这表明我们应该在女性癌症恶病质的早期阶段将非肌肉组织置于非肌肉组织上。我们注意到与骨骼肌收缩和线粒体功能有关的潜在保护机制。我们的发现,强调生物学性别之间癌症恶病质发作的可能异质性，这表明需要性别特异性方法来治疗癌症恶病质。
方法：8周龄BALB/c小鼠（69只雄性，59名女性)接受皮下C26同种异体移植物或PBS载体。肿瘤发展为10-，15-,20-,或25天。收集肌肉和器官，体内肌肉收缩力，蛋白质合成率，线粒体功能，和蛋白质周转标志物进行了评估。进行了性别内部的单向方差分析和性别之间的趋势分析，p<0.05。
结果：雄性小鼠的腓肠肌和TA肌肉在25天开始萎缩，尽管存在癌症恶病质的标志（脂肪减少，肝脾肿大）。我们观察到男性肌肉收缩性和蛋白质合成降低，伴随着肌肉质量衰减，在男女肌肉中具有较高的蛋白水解标记。在TA中Opa1的mRNA较低，而雄性小鼠25天后腓肠肌中的Bnip3较高，对雌性小鼠无显著影响。
结论：我们的数据表明，与男性相比，女性对骨骼肌的相对保护，尽管有其他癌症恶病质的典型迹象和蛋白质降解标志物增加；这表明我们应该在女性癌症恶病质的早期阶段将非肌肉组织置于非肌肉组织上。我们注意到与骨骼肌收缩和线粒体功能有关的潜在保护机制。我们的发现,强调生物学性别之间癌症恶病质发作的可能异质性，这表明需要性别特异性方法来治疗癌症恶病质。
