Department of Exercise Science and Health Promotion, Florida Atlantic University, Boca Raton, Florida, USA.
Rehabilitation Clinical Trials Center, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA.
Cell Biochem Funct. 2021 Aug;39(6):802-812. doi: 10.1002/cbf.3652. Epub 2021 Jun 15.
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. SIGNIFICANCE OF THE STUDY: Cachexia is a serious complication of cancer characterized by severe weight loss, muscle atrophy and frailty. Cachexia occurs in roughly half of all cancer patients, and in up to 80% of patients with advanced disease. Cachexia independently worsens patient prognosis, lowers treatment efficacy, increases hospitalization cost and length of stay, and accounts for 20-30% of cancer-related deaths. There are no effective treatments. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumour contribute to metabolic disruption and weight loss in cancer cachexia. Identifying therapies that normalize dysregulated substrate shuttling among energy-regulating tissues may protect against cachexia-related weight loss.
能量效率低下的器官间底物穿梭被认为是导致恶病质相关体重减轻的原因之一。在这里，我们研究了患有恶病质相关体重减轻的小鼠的骨骼肌、肝脏和肿瘤中的糖酵解途径代谢物、酶活性和转运蛋白，这些小鼠的体重减轻是由结肠 26 癌细胞引起的。患有恶病质的小鼠的骨骼肌中[L-乳酸]/[丙酮酸]、LDH 活性和乳酸转运蛋白 MCT1 增加。恶病质的肝脏也显示出增加的 MCT1。这与肌肉来源的乳酸向肝脏转移用于糖异生的速率增加的观点一致，即体重减轻的恶病质小鼠中的科里循环通量增加。肝脏和肿瘤之间的第二个穿梭也可能导致能量平衡和体重减轻的破坏。我们发现肿瘤中高亲和力葡萄糖转运蛋白 GLUT1 增加，表明活跃的葡萄糖摄取，肿瘤 MCT1 检测和肿瘤内[L-乳酸]/[丙酮酸]减少，暗示乳酸外排增加和/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（“反向瓦伯格效应”），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紊乱和体重减轻。旨在使能量调节组织中失调的底物穿梭正常化的治疗方法可能会缓解癌症恶病质中不必要的体重减轻。
恶病质是癌症的一种严重并发症，其特征是严重的体重减轻、肌肉萎缩和虚弱。恶病质发生在大约一半的癌症患者中，在进展期疾病患者中高达 80%。恶病质独立地恶化患者的预后，降低治疗效果，增加住院费用和住院时间，并占癌症相关死亡的 20-30%。目前尚无有效的治疗方法。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癌症恶病质中的代谢紊乱和体重减轻。确定使能量调节组织中失调的底物穿梭正常化的治疗方法可能有助于预防恶病质相关的体重减轻。
