AMPK is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice

Research output: Working paperPreprintResearch

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AMPK is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice. / Raun, Steffen Henning; Ali, Mona Sadek; Han, Xiuqing; Henríquez-Olguín, Carlos; Pham, Tang Cam Phung; Knudsen, Jonas Roland; Willemsen, Anna C H; Larsen, Steen; Jensen, Thomas Elbenhardt; Langen, Ramon; Sylow, Lykke.

bioRxiv, 2022.

Research output: Working paperPreprintResearch

Harvard

Raun, SH, Ali, MS, Han, X, Henríquez-Olguín, C, Pham, TCP, Knudsen, JR, Willemsen, ACH, Larsen, S, Jensen, TE, Langen, R & Sylow, L 2022 'AMPK is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice' bioRxiv. https://doi.org/10.1101/2022.06.07.495096

APA

Raun, S. H., Ali, M. S., Han, X., Henríquez-Olguín, C., Pham, T. C. P., Knudsen, J. R., Willemsen, A. C. H., Larsen, S., Jensen, T. E., Langen, R., & Sylow, L. (2022). AMPK is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice. bioRxiv. https://doi.org/10.1101/2022.06.07.495096

Vancouver

Raun SH, Ali MS, Han X, Henríquez-Olguín C, Pham TCP, Knudsen JR et al. AMPK is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice. bioRxiv. 2022 Jun 7. https://doi.org/10.1101/2022.06.07.495096

Author

Raun, Steffen Henning ; Ali, Mona Sadek ; Han, Xiuqing ; Henríquez-Olguín, Carlos ; Pham, Tang Cam Phung ; Knudsen, Jonas Roland ; Willemsen, Anna C H ; Larsen, Steen ; Jensen, Thomas Elbenhardt ; Langen, Ramon ; Sylow, Lykke. / AMPK is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice. bioRxiv, 2022.

Bibtex

@techreport{337789a421054df4b160a2ceab67b00a,
title = "AMPK is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice",
abstract = "Background: Metabolic dysfunction and cancer cachexia are associated with poor cancer prognosis, yet the molecular mechanisms causing cancer-induced metabolic dysfunction and cachexia remain to be defined. A key link between metabolic- and muscle mass-regulation is adenosine monophosphate-activated protein kinase (AMPK). As AMPK could be a potential treatment, it is important to determine the function for AMPK in cancer-associated metabolic dysfunction and cachexia. Here we determined the function of AMPK in cancer-associated metabolic dysfunction, insulin resistance, and cachexia. Methods: In vastus lateralis muscle biopsies from pre-cachectic and cachectic patients with Non-Small-Cell Lung Carcinoma (NSCLC), AMPK signaling and expression were examined by immunoblotting. To investigate the role of muscle AMPK, male mice overexpressing a dominant-negative AMPKα2 (kinase-dead) specifically in striated muscle (mAMPK-KD) were inoculated with Lewis Lung Carcinoma (LLC) cells. In a subsequent cohort, male LLC-tumor-bearing mice were treated with/without 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as control. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose- and insulin tolerance tests, tissue-specific 2-deoxy-glucose (2-DG) uptake, and immunoblotting. Results: In muscle from patients with NSCLC, we found increased expression of AMPK subunits α1, α2, β2, γ1, and γ3; ranging from +27% to +79% compared to healthy control subjects. AMPK subunit expression correlated with indices of cachexia, including cross sectional area and weight loss. Tumor-bearing mAMPK-KD mice presented increased fat loss as well as glucose and insulin intolerance. LLC in mAMPK-KD mice displayed lower insulin-stimulated 2-DG uptake in skeletal muscle (quadriceps; -35%, soleus; -49%, EDL; -48%) and the heart (-29%) compared to non-tumor-bearing mice. In skeletal muscle, mAMPK-KD abrogated the tumor-induced increase in phosphorylation of TBC1D4thr642. Additionally, protein expression of TBC1D4 (+26%), pyruvate dehydrogenase (PDH, +94%), and PDH-kinases (PDKs, +45% to +100%), and glycogen synthase (+48%) were increased in skeletal muscle of tumor-bearing mice in an AMPK-dependent manner. Lastly, chronic AICAR treatment elevated hexokinase-II protein expression and normalized phosphorylation of p70S6Kthr389 (mTORC1 substrate) and ACCser212 (AMPK substrate) and rescued the cancer-induced insulin intolerance. Conclusions: Upregulated protein expression of AMPK subunits observed in skeletal muscle of (pre)cachectic patients with non-small-cell lung carcinoma. This seemed protective inferred by AMPK-deficient tumor-bearing mice being highly prone to developing metabolic dysfunction, which included the AMPK-dependent regulation of several proteins involved in glucose metabolism. These observations highlight the potential for targeting AMPK to counter cancer-associated metabolic dysfunction and cachexia.",
keywords = "Faculty of Science, AMP-activated protein kinase (AMPK), Cancer cachexia, Skeletal muscle, Glucose metabolism, Insulin resistance",
author = "Raun, {Steffen Henning} and Ali, {Mona Sadek} and Xiuqing Han and Carlos Henr{\'i}quez-Olgu{\'i}n and Pham, {Tang Cam Phung} and Knudsen, {Jonas Roland} and Willemsen, {Anna C H} and Steen Larsen and Jensen, {Thomas Elbenhardt} and Ramon Langen and Lykke Sylow",
note = "bioRxiv preprint posted June 7, 2022.",
year = "2022",
month = jun,
day = "7",
doi = "10.1101/2022.06.07.495096",
language = "English",
publisher = "bioRxiv",
type = "WorkingPaper",
institution = "bioRxiv",

}

RIS

TY - UNPB

T1 - AMPK is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice

AU - Raun, Steffen Henning

AU - Ali, Mona Sadek

AU - Han, Xiuqing

AU - Henríquez-Olguín, Carlos

AU - Pham, Tang Cam Phung

AU - Knudsen, Jonas Roland

AU - Willemsen, Anna C H

AU - Larsen, Steen

AU - Jensen, Thomas Elbenhardt

AU - Langen, Ramon

AU - Sylow, Lykke

N1 - bioRxiv preprint posted June 7, 2022.

PY - 2022/6/7

Y1 - 2022/6/7

N2 - Background: Metabolic dysfunction and cancer cachexia are associated with poor cancer prognosis, yet the molecular mechanisms causing cancer-induced metabolic dysfunction and cachexia remain to be defined. A key link between metabolic- and muscle mass-regulation is adenosine monophosphate-activated protein kinase (AMPK). As AMPK could be a potential treatment, it is important to determine the function for AMPK in cancer-associated metabolic dysfunction and cachexia. Here we determined the function of AMPK in cancer-associated metabolic dysfunction, insulin resistance, and cachexia. Methods: In vastus lateralis muscle biopsies from pre-cachectic and cachectic patients with Non-Small-Cell Lung Carcinoma (NSCLC), AMPK signaling and expression were examined by immunoblotting. To investigate the role of muscle AMPK, male mice overexpressing a dominant-negative AMPKα2 (kinase-dead) specifically in striated muscle (mAMPK-KD) were inoculated with Lewis Lung Carcinoma (LLC) cells. In a subsequent cohort, male LLC-tumor-bearing mice were treated with/without 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as control. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose- and insulin tolerance tests, tissue-specific 2-deoxy-glucose (2-DG) uptake, and immunoblotting. Results: In muscle from patients with NSCLC, we found increased expression of AMPK subunits α1, α2, β2, γ1, and γ3; ranging from +27% to +79% compared to healthy control subjects. AMPK subunit expression correlated with indices of cachexia, including cross sectional area and weight loss. Tumor-bearing mAMPK-KD mice presented increased fat loss as well as glucose and insulin intolerance. LLC in mAMPK-KD mice displayed lower insulin-stimulated 2-DG uptake in skeletal muscle (quadriceps; -35%, soleus; -49%, EDL; -48%) and the heart (-29%) compared to non-tumor-bearing mice. In skeletal muscle, mAMPK-KD abrogated the tumor-induced increase in phosphorylation of TBC1D4thr642. Additionally, protein expression of TBC1D4 (+26%), pyruvate dehydrogenase (PDH, +94%), and PDH-kinases (PDKs, +45% to +100%), and glycogen synthase (+48%) were increased in skeletal muscle of tumor-bearing mice in an AMPK-dependent manner. Lastly, chronic AICAR treatment elevated hexokinase-II protein expression and normalized phosphorylation of p70S6Kthr389 (mTORC1 substrate) and ACCser212 (AMPK substrate) and rescued the cancer-induced insulin intolerance. Conclusions: Upregulated protein expression of AMPK subunits observed in skeletal muscle of (pre)cachectic patients with non-small-cell lung carcinoma. This seemed protective inferred by AMPK-deficient tumor-bearing mice being highly prone to developing metabolic dysfunction, which included the AMPK-dependent regulation of several proteins involved in glucose metabolism. These observations highlight the potential for targeting AMPK to counter cancer-associated metabolic dysfunction and cachexia.

AB - Background: Metabolic dysfunction and cancer cachexia are associated with poor cancer prognosis, yet the molecular mechanisms causing cancer-induced metabolic dysfunction and cachexia remain to be defined. A key link between metabolic- and muscle mass-regulation is adenosine monophosphate-activated protein kinase (AMPK). As AMPK could be a potential treatment, it is important to determine the function for AMPK in cancer-associated metabolic dysfunction and cachexia. Here we determined the function of AMPK in cancer-associated metabolic dysfunction, insulin resistance, and cachexia. Methods: In vastus lateralis muscle biopsies from pre-cachectic and cachectic patients with Non-Small-Cell Lung Carcinoma (NSCLC), AMPK signaling and expression were examined by immunoblotting. To investigate the role of muscle AMPK, male mice overexpressing a dominant-negative AMPKα2 (kinase-dead) specifically in striated muscle (mAMPK-KD) were inoculated with Lewis Lung Carcinoma (LLC) cells. In a subsequent cohort, male LLC-tumor-bearing mice were treated with/without 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as control. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose- and insulin tolerance tests, tissue-specific 2-deoxy-glucose (2-DG) uptake, and immunoblotting. Results: In muscle from patients with NSCLC, we found increased expression of AMPK subunits α1, α2, β2, γ1, and γ3; ranging from +27% to +79% compared to healthy control subjects. AMPK subunit expression correlated with indices of cachexia, including cross sectional area and weight loss. Tumor-bearing mAMPK-KD mice presented increased fat loss as well as glucose and insulin intolerance. LLC in mAMPK-KD mice displayed lower insulin-stimulated 2-DG uptake in skeletal muscle (quadriceps; -35%, soleus; -49%, EDL; -48%) and the heart (-29%) compared to non-tumor-bearing mice. In skeletal muscle, mAMPK-KD abrogated the tumor-induced increase in phosphorylation of TBC1D4thr642. Additionally, protein expression of TBC1D4 (+26%), pyruvate dehydrogenase (PDH, +94%), and PDH-kinases (PDKs, +45% to +100%), and glycogen synthase (+48%) were increased in skeletal muscle of tumor-bearing mice in an AMPK-dependent manner. Lastly, chronic AICAR treatment elevated hexokinase-II protein expression and normalized phosphorylation of p70S6Kthr389 (mTORC1 substrate) and ACCser212 (AMPK substrate) and rescued the cancer-induced insulin intolerance. Conclusions: Upregulated protein expression of AMPK subunits observed in skeletal muscle of (pre)cachectic patients with non-small-cell lung carcinoma. This seemed protective inferred by AMPK-deficient tumor-bearing mice being highly prone to developing metabolic dysfunction, which included the AMPK-dependent regulation of several proteins involved in glucose metabolism. These observations highlight the potential for targeting AMPK to counter cancer-associated metabolic dysfunction and cachexia.

KW - Faculty of Science

KW - AMP-activated protein kinase (AMPK)

KW - Cancer cachexia

KW - Skeletal muscle

KW - Glucose metabolism

KW - Insulin resistance

U2 - 10.1101/2022.06.07.495096

DO - 10.1101/2022.06.07.495096

M3 - Preprint

BT - AMPK is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice

PB - bioRxiv

ER -

ID: 310228526