Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type-specific manner
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Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type-specific manner. / Raun, Steffen Henning; Knudsen, Jonas Roland; Han, Xiuqing; Jensen, Thomas Elbenhardt; Sylow, Lykke.
In: F A S E B Journal, Vol. 36, No. 3, e22211, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type-specific manner
AU - Raun, Steffen Henning
AU - Knudsen, Jonas Roland
AU - Han, Xiuqing
AU - Jensen, Thomas Elbenhardt
AU - Sylow, Lykke
N1 - © 2022 Federation of American Societies for Experimental Biology.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Faculty of Science
KW - Akt
KW - AMPK
KW - Cachexia
KW - Cancer
KW - Glucose metabolism
KW - Insulin resistance
KW - Lewis lung carcinoma
KW - Muscle
KW - mTORC1
KW - TBC1D4
U2 - 10.1096/fj.202101759R
DO - 10.1096/fj.202101759R
M3 - Journal article
C2 - 35195922
VL - 36
JO - F A S E B Journal
JF - F A S E B Journal
SN - 0892-6638
IS - 3
M1 - e22211
ER -
ID: 297956733