ORCID Profile
0000-0002-5170-4337
Current Organisations
IT University of Copenhagen
,
Medical University of Białystok
,
Københavns Universitet
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Publisher: Elsevier BV
Date: 12-2021
Publisher: Frontiers Media SA
Date: 2012
Publisher: Cold Spring Harbor Laboratory
Date: 07-06-2022
DOI: 10.1101/2022.06.07.495096
Abstract: 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. 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. 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 TBC1D4 thr642 . 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 p70S6K thr389 (mTORC1 substrate) and ACC ser212 (AMPK substrate) and rescued the cancer-induced insulin intolerance. 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.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-09-2020
Abstract: Aerobic exercise elicits an integrated metabolic response that involves multiple tissues and confers beneficial effects to metabolic health. Here we found that this integrative response involves energy-sensing pathways in muscle and fat and circulating factors that lead to the upregulation of the type III endoribonuclease DICER in adipose tissue and the consequent increase of microRNAs. Upon upregulation, DICER and the microRNA-203-3p inhibit glucose utilization by fat cells and favor oxidative metabolism. In turn, this supports the exercised muscle with adequate substrate availability. When this pathway is disrupted, whole-body metabolism is affected, and exercise performance is impaired. Thus, adipose tissue DICER integrates signals from the exercising muscle to allow a proper metabolic response to exercise training.
Publisher: Wiley
Date: 26-12-2019
DOI: 10.1113/JP278752
Publisher: Cold Spring Harbor Laboratory
Date: 30-10-2023
Publisher: Wiley
Date: 19-12-2017
DOI: 10.1111/APHA.13009
Abstract: Metabolic health may deteriorate with age as a result of altered body composition and decreased physical activity. Endurance exercise is known to counter these changes delaying or even preventing onset of metabolic diseases. High-intensity interval training (HIIT) is a time efficient alternative to regular endurance exercise, and the aim of this study was to investigate the metabolic benefit of HIIT in older subjects. Twenty-two sedentary male (n = 11) and female (n = 11) subjects aged 63 ± 1 years performed HIIT training three times/week for 6 weeks on a bicycle ergometer. Each HIIT session consisted of five 1-minute intervals interspersed with 1½-minute rest. Prior to the first and after the last HIIT session whole-body insulin sensitivity, measured by a hyperinsulinaemic-euglycaemic cl , plasma lipid levels, HbA1c, glycaemic parameters, body composition and maximal oxygen uptake were assessed. Muscle biopsies were obtained wherefrom content of glycogen and proteins involved in muscle glucose handling were determined. Insulin sensitivity (P = .011) and maximal oxygen uptake increased (P < .05) in both genders, while plasma cholesterol (P < .05), low-density lipoprotein (P < .05), visceral fat mass (P < .05) and per cent body fat (P < .05) decreased after 6 weeks of HIIT. HbA1c decreased only in males (P = .001). Muscle glycogen content increased in both genders (P = .001) and in line GLUT4 (P < .05), glycogen synthase (P = .001) and hexokinase II (P < .05) content all increased. Six weeks of HIIT significantly improves metabolic health in older males and females by reducing age-related risk factors for cardiometabolic disease.
Publisher: Springer Science and Business Media LLC
Date: 26-03-2021
Publisher: Elsevier BV
Date: 11-2021
Publisher: American Physiological Society
Date: 04-2018
DOI: 10.1152/AJPENDO.00213.2017
Abstract: Nicotinamide adenine dinucleotide (NAD + ) can be synthesized by nicotinamide phosphoribosyltransferase (NAMPT). We aimed to determine the role of NAMPT in maintaining NAD + levels, mitochondrial function, and metabolic homeostasis in skeletal muscle cells. We generated stable N t knockdown (sh N t KD) C2C12 cells using a shRNA lentiviral approach. Moreover, we applied gene electrotransfer to express Cre recombinase in tibialis anterior muscle of floxed N t mice. In sh N t KD C2C12 myoblasts, N t and NAD + levels were reduced by 70% and 50%, respectively, and maximal respiratory capacity was reduced by 25%. Moreover, anaerobic glycolytic flux increased by 55%, and 2-deoxyglucose uptake increased by 25% in sh N t KD cells. Treatment with the NAD + precursor nicotinamide riboside restored NAD + levels in sh N t cells and increased maximal respiratory capacity by 18% and 32% in control and sh N t KD cells, respectively. Expression of Cre recombinase in muscle of floxed N t mice reduced NAMPT and NAD + levels by 38% and 43%, respectively. Glucose uptake increased by 40%, and mitochondrial complex IV respiration was compromised by 20%. Hypoxia-inducible factor (HIF)-1α-regulated genes and histone H3 lysine 9 (H3K9) acetylation, a known sirtuin 6 (SIRT6) target, were increased in shN t KD cells. Thus, we propose that the shift toward glycolytic metabolism observed, at least in part, is mediated by the SIRT6/HIF1α axis. Our findings suggest that NAMPT plays a key role for maintaining NAD + levels in skeletal muscle and that NAMPT deficiency compromises oxidative phosphorylation capacity and alters energy homeostasis in this tissue.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2020
No related grants have been discovered for Steen Larsen.