Distinct glycolytic pathway regulation in liver, tumour and skeletal muscle of mice with cancer cachexia.
Distinct glycolytic pathway regulation in liver, tumour and skeletal muscle of mice with cancer cachexia.
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DOI：
10.1002/cbf.3652
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发表时间：
2021-08
影响因子：
3.6
通讯作者：
Khamoui AV
中科院分区：
文献类型：
--
作者：
Visavadiya NP;Rossiter HB;Khamoui AV
能量效率低的器官间基质穿梭被认为是恶病质相关体重减轻的贡献者。在这里，我们研究了结肠癌26细胞诱导恶病质相关体重减轻的小鼠骨骼肌、肝脏和肿瘤中的糖酵解途径代谢物、酶活性和转运蛋白。恶病质小鼠的骨骼肌[L-乳酸]/[丙酮酸]、LDH活性和乳酸转运蛋白MCT 1增加。恶病质肝脏也显示MCT 1增加。这与肌源性乳酸穿梭至肝脏以用于肝再生的速率增加的提议一致，即在减肥恶病质小鼠中增加的科里循环通量。肝脏和肿瘤之间的第二次穿梭也可能导致能量平衡中断和体重减轻。我们发现肿瘤中高亲和力葡萄糖转运蛋白GLUT 1增加，表明葡萄糖摄取活跃，肿瘤MCT 1检测和肿瘤内[L-乳酸]/[丙酮酸]降低，这意味着乳酸流出和/或肿瘤内乳酸氧化增加。最后，恶病质肌肉中的高[L-乳酸]/[丙酮酸]和MCT 1为肿瘤提供了潜在的肌肉来源的乳酸供应（“反向瓦尔堡效应”），支持肿瘤生长和随后的恶病质。我们的研究结果表明，肝脏，骨骼肌和肿瘤之间的几种底物穿梭有助于代谢中断和体重减轻。旨在使能量调节组织之间的失调底物穿梭正常化的治疗可能会减轻癌症恶病质中的意外体重减轻。
Energetically inefficient inter-organ substrate shuttles are proposed contributors to cachexia-related weight loss. Here we examined glycolytic pathway metabolites, enzyme activity, and transport proteins in skeletal muscle, liver and tumors of mice with cachexia-related weight loss induced by colon-26 cancer cells. Skeletal muscle of cachexic mice had increased [L-lactate]/[pyruvate], LDH activity, and lactate transporter MCT1. Cachexic livers also showed increased MCT1. This is consistent with the proposal that the rate of muscle-derived lactate shuttling to liver for use in gluconeogenesis is increased i.e. an increased Cori cycle flux in weight-losing cachexic mice. A second shuttle between liver and tumor may also contribute to disrupted energy balance and weight loss. We found increased high-affinity glucose transporter GLUT1 in tumors, suggesting active glucose uptake, tumor MCT1 detection and decreased intratumor [L-lactate]/[pyruvate], implying increased lactate efflux and/or intratumor lactate oxidation. Last, high [L-lactate]/[pyruvate] and MCT1 in cachexic muscle provides a potential muscle-derived lactate supply for the tumor (a “reverse Warburg effect”), supporting tumor growth and consequent cachexia. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumor contribute to metabolic disruption and weight loss. Therapies that aim to normalize dysregulated substrate shuttling among energy-regulating tissues may alleviate unintended weight loss in cancer cachexia.
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影响因子：
9.8
作者：
Khamoui, Andy V.;Park, Bong-Sup;Kim, Jeong-Su
通讯作者：
Kim, Jeong-Su
影响因子：
15.9
作者：
Acharyya, S;Ladner, KJ;Guttridge, DC
通讯作者：
Guttridge, DC
影响因子：
64.5
作者：
Faubert B;Li KY;Cai L;Hensley CT;Kim J;Zacharias LG;Yang C;Do QN;Doucette S;Burguete D;Li H;Huet G;Yuan Q;Wigal T;Butt Y;Ni M;Torrealba J;Oliver D;Lenkinski RE;Malloy CR;Wachsmann JW;Young JD;Kernstine K;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
3.8
作者：
Bachmann J;Ketterer K;Marsch C;Fechtner K;Krakowski-Roosen H;Büchler MW;Friess H;Martignoni ME
通讯作者：
Martignoni ME
影响因子：
4
作者：
Manring H;Abreu E;Brotto L;Weisleder N;Brotto M
通讯作者：
Brotto M