Cancer causes dysfunctional insulin signaling and glucose transport in a muscle‐type‐specific manner

• Published in: The FASEB journal Vol. 36; no. 3; pp. e22211 - n/a
• Main Authors: Raun, Steffen H., Knudsen, Jonas Roland, Han, Xiuqing, Jensen, Thomas E., Sylow, Lykke
• Format: Journal Article
• Language: English
• Published: United States 01-03-2022
• Subjects: Akt; AMP-Activated Protein Kinase Kinases - metabolism; AMPK; Animals; Autophagy-Related Protein-1 Homolog - metabolism; Biological Transport; cachexia; cancer; Carcinoma, Lewis Lung - metabolism; Cell Line, Tumor; Female; Glucose - metabolism; Glycogen Synthase Kinase 3 beta - metabolism; GTPase-Activating Proteins - metabolism; insulin resistance; Insulin Secretion; Lewis lung carcinoma; Mice; Mice, Inbred C57BL; mTORC1; muscle; Muscle, Skeletal - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction; TBC1D4; TOR Serine-Threonine Kinases - metabolism; Lewis lung carcinoma; TBC1D4; cachexia; muscle; AMPK; cancer; Akt; glucose metabolism; insulin resistance; mTORC1
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202101759R

Metabolic dysfunction and insulin resistance are emerging as hallmarks of cancer and cachexia, and impair cancer prognosis. Yet, the molecular mechanisms underlying impaired metabolic regulation are not fully understood. To elucidate the mechanisms behind cancer‐induced insulin resistance in muscle, we isolated extensor digitorum longus (EDL) and soleus muscles from Lewis Lung Carcinoma tumor‐bearing mice. Three weeks after tumor inoculation, muscles were isolated and stimulated with or without a submaximal dose of insulin (1.5 nM). Glucose transport was measured using 2‐[3H]Deoxy‐Glucose and intramyocellular signaling was investigated using immunoblotting. In soleus muscles from tumor‐bearing mice, insulin‐stimulated glucose transport was abrogated concomitantly with abolished insulin‐induced TBC1D4 and GSK3 phosphorylation. In EDL, glucose transport and TBC1D4 phosphorylation were not impaired in muscles from tumor‐bearing mice, while AMPK signaling was elevated. Anabolic insulin signaling via phosphorylation of the mTORC1 targets, p70S6K thr389, and ribosomal‐S6 ser235, were decreased by cancer in soleus muscle while increased or unaffected in EDL. In contrast, the mTOR substrate, pULK1 ser757, was reduced in both soleus and EDL by cancer. Hence, cancer causes considerable changes in skeletal muscle insulin signaling that is dependent on muscle‐type, which could contribute to metabolic dysregulation in cancer. Thus, the skeletal muscle could be a target for managing metabolic dysfunction in cancer.