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 tumours 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, that is, an increased Cori cycle flux in weight-losing cachexic mice. A second shuttle between liver and tumour may also contribute to disrupted energy balance and weight loss. We found increased high-affinity glucose transporter GLUT1 in tumours, suggesting active glucose uptake, tumour MCT1 detection and decreased intratumour [L-lactate]/[pyruvate], implying increased lactate efflux and/or intratumour lactate oxidation. Last, high [L-lactate]/[pyruvate] and MCT1 in cachexic muscle provides a potential muscle-derived lactate supply for the tumour (a ‘reverse Warburg effect’), supporting tumour growth and consequent cachexia. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumour 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.

中文翻译：

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癌症恶病质小鼠肝脏、肿瘤和骨骼肌中不同的糖酵解途径调控

能量效率低下的器官间底物穿梭被认为是恶病质相关体重减轻的贡献者。在这里，我们检测了结肠 26 癌细胞诱导的恶病质相关体重减轻小鼠骨骼肌、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增加了[L-乳酸]/[丙酮酸]、LDH 活性和乳酸转运蛋白 MCT1。恶病质肝脏也显示 MCT1 增加。这与肌肉来源的乳酸穿梭到肝脏用于糖异生的速率增加的提议是一致的，也就是说，体重减轻的恶病质小鼠的 Cori 循环通量增加。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 GLUT1 增加，表明葡萄糖摄取活跃，肿瘤 MCT1 检测和肿瘤内 [L-乳酸]/[丙酮酸] 减少，这意味着乳酸外流和/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 MCT1 为肿瘤提供了潜在的肌肉来源的乳酸供应（“反向 Warburg 效应”），支持肿瘤生长和随之而来的恶病质。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紊乱和体重减轻。旨在使能量调节组织之间失调的底物穿梭正常化的疗法可能会减轻癌症恶病质中的意外体重减轻。意味着增加的乳酸流出和/或瘤内乳酸氧化。最后，恶病质肌肉中的高 [L-乳酸]/[丙酮酸] 和 MCT1 为肿瘤提供了潜在的肌肉来源的乳酸供应（“反向 Warburg 效应”），支持肿瘤生长和随之而来的恶病质。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紊乱和体重减轻。旨在使能量调节组织之间失调的底物穿梭正常化的疗法可能会减轻癌症恶病质中的意外体重减轻。意味着增加的乳酸流出和/或瘤内乳酸氧化。最后，恶病质肌肉中的高 [L-乳酸]/[丙酮酸] 和 MCT1 为肿瘤提供了潜在的肌肉来源的乳酸供应（“反向 Warburg 效应”），支持肿瘤生长和随之而来的恶病质。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紊乱和体重减轻。旨在使能量调节组织之间失调的底物穿梭正常化的疗法可能会减轻癌症恶病质中的意外体重减轻。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紊乱和体重减轻。旨在使能量调节组织之间失调的底物穿梭正常化的疗法可能会减轻癌症恶病质中的意外体重减轻。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紊乱和体重减轻。旨在使能量调节组织之间失调的底物穿梭正常化的疗法可能会减轻癌症恶病质中的意外体重减轻。