Molecular metabolism · 2026
Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.
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Frank Emma, Persson Kaspar W, Morigny Pauline, Ogueboule Zakarias Kefil Jensen, Pham Tang Cam Phung, Knudsen Jonas R, Rohm Maria, Sylow Lykke, Raun Steffen H
Аннотация
PURPOSE: Cancer cachexia is a life-threatening complication of advanced malignancies, driven by profound systemic metabolic reprogramming and anorexia. Insulin action is markedly impaired in patients with cancer and may contribute directly to cachexia pathogenesis. However, the interplay between weight loss, food intake, and cancer-associated metabolic rewiring in cachexia remains poorly defined. Clarifying this relationship is essential for identifying the fundamental drivers of cachexia and for developing effective therapeutic strategies.
METHODS: We assessed metabolic rewiring by temporal evaluation of glucose tolerance and isotopic tracers to determine muscle insulin-stimulated glucose uptake in male cachectic and non-cachectic C26- and KPC-tumor-bearing, as well as healthy mice undergoing food restriction.
RESULTS: Cachectic C26- and KPC-tumor mice showed increased glucose tolerance compared to non-tumor-bearing control mice, and non-cachectic tumor-bearing mice. Increased glucose tolerance appeared prior to overt muscle loss, independent of tumor size and changes in food intake. Ex vivo insulin-stimulated glucose uptake was elevated in soleus (+78%) and extensor digitorum longus (+35%) muscle from cachectic C26-tumor mice with anorexia compared to weight stable C26-tumor mice and control mice. This increase was associated with enhanced AKT signaling. Food restriction in healthy mice increased glucose tolerance, insulin-stimulated glucose uptake ex vivo, and AKT signaling.
CONCLUSIONS: Our findings suggest that glucose hypermetabolism appears prior to overt weight loss in pre-clinical cachexia, whereas late-stage cachexia with anorexia increased skeletal muscle insulin responsiveness. This highlights AKT signaling as a key node connecting nutrient status with muscle metabolism in cancer cachexia.
METHODS: We assessed metabolic rewiring by temporal evaluation of glucose tolerance and isotopic tracers to determine muscle insulin-stimulated glucose uptake in male cachectic and non-cachectic C26- and KPC-tumor-bearing, as well as healthy mice undergoing food restriction.
RESULTS: Cachectic C26- and KPC-tumor mice showed increased glucose tolerance compared to non-tumor-bearing control mice, and non-cachectic tumor-bearing mice. Increased glucose tolerance appeared prior to overt muscle loss, independent of tumor size and changes in food intake. Ex vivo insulin-stimulated glucose uptake was elevated in soleus (+78%) and extensor digitorum longus (+35%) muscle from cachectic C26-tumor mice with anorexia compared to weight stable C26-tumor mice and control mice. This increase was associated with enhanced AKT signaling. Food restriction in healthy mice increased glucose tolerance, insulin-stimulated glucose uptake ex vivo, and AKT signaling.
CONCLUSIONS: Our findings suggest that glucose hypermetabolism appears prior to overt weight loss in pre-clinical cachexia, whereas late-stage cachexia with anorexia increased skeletal muscle insulin responsiveness. This highlights AKT signaling as a key node connecting nutrient status with muscle metabolism in cancer cachexia.