Parry Traci L, Wood Nicole, Garritson Jacob, Muehlbauer Michael J, Tichy Louisa, Brantley Jason T, Bain James R, Hayward Reid
Department of Kinesiology, University of North Carolina Greensboro, Greensboro, North Carolina, USA.
Department of Kinesiology, Nutrition, and Dietetics, and the University of Northern Colorado Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, Colorado, USA.
Cancer Rep (Hoboken). 2025 Sep;8(9):e70290. doi: 10.1002/cnr2.70290.
Cancer cachexia is a metabolic and wasting disease that occurs in up to 80% of cancer patients. Currently, there are no clear diagnostic criteria, its effects are irreversible, and it cannot be treated. Most patients progress undetected to late stages of cancer cachexia, stop responding to traditional treatment, and die without an effective intervention. While the literature has begun to characterize late (refractory) cachexia muscle metabolic changes, less is known about early changes that may precede obvious muscle dysfunction and wasting. Therefore, this investigation aimed to characterize early phase heart and skeletal muscle metabolic changes in a preclinical model of colorectal cancer.
The Apc(min/+) mouse spontaneously forms tumors along the intestinal tract and is a well-accepted preclinical colorectal cancer model. To identify early changes in muscle metabolism during colorectal cancer development, heart and gastrocnemius tissues from 15-week-old male Apc(min/+) and litter-matched non-carrier mice (wildtype) were analyzed by untargeted GC/MS metabolomics.
In the heart, metabolic pathways related to taurine/hypotaurine metabolism; biosynthesis of unsaturated fatty acids; alanine, glutamate, and aspartate; arginine and proline; and arginine biosynthesis were affected by colorectal cancer. In skeletal muscle, metabolic pathways involving arginine biosynthesis; alanine, glutamate, aspartate, and proline metabolism were affected by cancer cachexia. Taken together, these data demonstrate altered arginine metabolism and proline metabolism in hearts and skeletal muscle of cachectic mice. Interestingly, cardiac muscle showed a non-preferential fuel switch towards less energetically favorable glycolysis (vs. fatty acid metabolism) that coincided with cardiac dysfunction, while skeletal muscle exhibited glucose dysregulation and possible insulin resistance.
These data characterize early cardiac and skeletal muscle metabolic derangements that lead to muscle dysfunction and atrophy during colorectal cancer. Such data could help identify patients in early phases of cachexia or identification of cardiac and skeletal muscle specific therapeutic targets aimed at early intervention.
癌症恶病质是一种代谢性消耗疾病，高达80%的癌症患者会出现。目前，尚无明确的诊断标准，其影响是不可逆的，且无法治疗。大多数患者在未被察觉的情况下进展至癌症恶病质晚期，对传统治疗不再有反应，最终在没有有效干预的情况下死亡。虽然已有文献开始描述晚期（难治性）恶病质肌肉代谢变化，但对于在明显肌肉功能障碍和消瘦之前可能出现的早期变化了解较少。因此，本研究旨在描述结直肠癌临床前模型中早期心脏和骨骼肌的代谢变化。
Apc(min/+)小鼠会在肠道自发形成肿瘤，是一种广泛接受的结直肠癌临床前模型。为了识别结直肠癌发展过程中肌肉代谢的早期变化，对15周龄雄性Apc(min/+)小鼠和同窝匹配的非携带者小鼠（野生型）的心脏和腓肠肌组织进行了非靶向气相色谱/质谱代谢组学分析。
在心脏中，与牛磺酸/亚牛磺酸代谢、不饱和脂肪酸生物合成、丙氨酸、谷氨酸和天冬氨酸、精氨酸和脯氨酸以及精氨酸生物合成相关的代谢途径受到结直肠癌的影响。在骨骼肌中，涉及精氨酸生物合成、丙氨酸、谷氨酸、天冬氨酸和脯氨酸代谢的代谢途径受到癌症恶病质的影响。综合来看，这些数据表明恶病质小鼠的心脏和骨骼肌中精氨酸代谢和脯氨酸代谢发生了改变。有趣的是，心肌表现出向能量利用效率较低的糖酵解（相对于脂肪酸代谢）的非优先燃料转换，这与心脏功能障碍同时出现，而骨骼肌则表现出葡萄糖调节异常和可能的胰岛素抵抗。
这些数据描述了结直肠癌期间导致肌肉功能障碍和萎缩的早期心脏和骨骼肌代谢紊乱。这些数据有助于识别恶病质早期阶段的患者，或确定针对早期干预的心脏和骨骼肌特异性治疗靶点。
