Skeletal muscle-specific over-expression of the nuclear sirtuin SIRT6 blocks cancer-associated cachexia by regulating multiple targets.
Skeletal muscle-specific over-expression of the nuclear sirtuin SIRT6 blocks cancer-associated cachexia by regulating multiple targets.
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DOI：
10.1002/rco2.27
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发表时间：
2021-01
影响因子：
--
通讯作者：
Gupta MP
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文献类型：
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作者：
Samant SA;Pillai VB;Gupta MP
在癌症恶病质期间，从肿瘤细胞释放的细胞因子可以改变身体的代谢，这可以导致这种疾病过程的发作。恶病质的生物学基础是多因素的，因此，识别和调节多个靶点以缩短恶病质的过程是重要的。以前，我们报道了核sirtuin，SIRT 6，通过调节NF-κB信号传导阻断肌肉生长抑制素的表达，肌肉生长抑制素是肌肉生长的负调节因子。进行这项研究是为了测试肌肉特异性过表达的SIRT 6是否可以在体内阻断癌症相关的肌肉萎缩，并确定SIRT 6的其他相关靶点，这可以解释其维持肌肉健康的能力。我们产生了骨骼肌特异性SIRT 6过表达转基因小鼠系（Sk.T6Tg），与其对照同窝仔相比，其以中等（2倍至4倍）水平表达SIRT 6。为了产生癌症恶病质模型，将B16 F10小鼠黑素瘤细胞皮下注射到小鼠的侧腹中。通过组织学、免疫印迹和RT-qPCR分析非肿瘤和肿瘤对照以及Sk.T6Tg小鼠（n = 5-20）的腓肠肌组织。在非肿瘤和肿瘤条件下，使用细胞因子阵列和ELISA评价小鼠的血浆样品。我们的结果证明了SIRT 6在癌症恶病质小鼠模型中肌肉特异性中度过表达的双重益处。在荷瘤小鼠中，SIRT 6过表达保留了肌肉重量（P < 0.001）和纤维大小（P < 0.005），并抑制了肿瘤生长（P < 0.05）。SIRT 6过表达显著降低了肌肉生长抑制素表达和血浆游离脂肪酸水平，但维持了荷瘤小鼠的血浆胰岛素水平。SIRT 6的这些积极作用与循环趋化因子CXCL 10和肌因子WNT 4的下调有关。SIRT 6还上调骨骼肌中主要葡萄糖转运蛋白GLUT 4的表达。这些结果首次证明SIRT 6调节多个靶点以限制肿瘤生长和癌症相关的肌肉萎缩。鉴于恶病质的多因素性质，同时控制多个通路的SIRT 6可以是克服这种衰弱综合征的有价值的治疗靶点。
During cancer cachexia, cytokines released from tumour cells can alter body's metabolism, which can lead to onset of this disease process. Biological basis of cachexia is multifactorial; hence, it is important to identify and modulate multiple targets to curtail the process of cachexia. Previously, we reported that the nuclear sirtuin, SIRT6, blocks expression of myostatin, a negative regulator of muscle growth, through modulation of the NF‐κB signalling. This study was undertaken to test whether muscle‐specific over‐expression of SIRT6 can block the cancer‐associated muscle wasting in vivo and to identify additional relevant targets of SIRT6, which can explain its ability to maintain muscle health. We generated a skeletal muscle‐specific SIRT6 over‐expressing transgenic mouse line (Sk.T6Tg) expressing SIRT6 at a moderate (two‐fold to four‐fold) level, compared with its control littermates. To generate a cancer‐cachexia model, B16F10 mouse melanoma cells were injected subcutaneously in the flanks of mice. Gastrocnemius muscle tissues from non‐tumour and tumour controls and Sk.T6Tg mice (n = 5–20) were analysed by histology, immunoblotting, and RT‐qPCR. Plasma samples of mice were evaluated using cytokine arrays and ELISA in both non‐tumour and tumour conditions. Our results demonstrate dual benefits of muscle‐specific moderate over‐expression of SIRT6 in a mouse model of cancer‐cachexia. In tumour‐bearing mice, SIRT6 over‐expression preserved muscle weight (P < 0.001) and fibre size (P < 0.005) as well as suppressed tumour growth (P < 0.05). SIRT6 over‐expression significantly reduced myostatin expression and plasma free fatty acids levels but maintained plasma insulin levels in tumour‐bearing mice. These positive effects of SIRT6 were associated with downregulation of the circulatory chemokine, CXCL10, and the myokine, WNT4. SIRT6 also upregulated expression of GLUT4, the major glucose transporter in the skeletal muscle. These results for the first time demonstrate that SIRT6 regulates multiple targets to limit tumour growth and cancer‐associated muscle atrophy. Given the multifactorial nature of cachexia, SIRT6, which concurrently controls multiple pathways, can be a valuable therapeutic target to overcome this debilitating syndrome.