Biology subjects

Thomassen, M.

Publications and source records attributed to Thomassen, M..

6 recordsLinked to original sources

bioRxiv2023

Insulin and Exercise-induced Phosphoproteomics of Human Skeletal Muscle Identify REPS1 as a New Regulator of Muscle Glucose Uptake

Skeletal muscle regulates glucose uptake in response to insulin and exercise which is critical for maintaining metabolic health. We conducted a comprehensive phosphoproteomic analysis of skeletal muscle from healthy people in response to an acute bout of exercise or insulin stimulation by a hyperinsulinemic euglycemic clamp. Our analysis revealed 233 phosphosites regulated by both exercise and insulin of which most phosphosites were regulated in opposite directions. However, 71 phosphosites on 55 proteins displayed regulation in the same direction, indicating a potential convergence of signaling pathways. We identified the vesicle-associated protein, REPS1, to be phosphorylated at Ser709 in response to both insulin and exercise. REPS1 protein level and Ser709 phosphorylation were closely related to insulin-stimulated glucose uptake in skeletal muscle and required for maximal insulin-stimulated glucose uptake. Furthermore, we observed that insulin triggered phosphorylation of REPS1 Ser709 via P90S6 kinase (RSK) and is impaired in mice and humans with insulin resistance. Collectively, REPS1 is a convergence point for insulin and exercise signaling and a promising therapeutic target in insulin resistance.

biochemistry↗

bioRxiv2023

Insight into spatial intratumoral genomic evolution in glioblastoma

Glioblastoma undergoes a complex and dynamic evolution involving genetic and epigenetic changes. Understanding the mechanisms underlying this evolution is vital for the development of efficient therapeutic strategies. Although treatment resistance is associated with intratumoral heterogeneity in glioblastoma, it remains uncertain whether hypometabolic and hypermetabolic lesions observed through positron emission tomography (PET) imaging are influenced by spatial intratumoral genomic evolution. In this study, we precisely isolated autologous hypometabolic and hypermetabolic lesions from glioblastoma using advanced neurosurgical and brain tumor imaging technologies, followed by comprehensive whole-genome exome and transcriptome analyses. Our findings revealed that hypermetabolic lesions evolved from hypometabolic lesions, harbored shrewd focal amplifications and deletions, and exhibited a higher frequency of critical genomic alterations linked to increased aggressiveness, upregulated APOBEC3 and hypoxic genes, and downregulated putative tumor suppressors. This study highlights spatial genomic evolution with diagnostic implications and unveils the obstacles and possibilities that should be considered in the development of novel therapeutic strategies. Statement of significanceGlioblastoma is a multifaceted disease that is difficult to treat, and insights into the metabolic gradient observed in imaging and the underlying role of genomic evolution are lacking. This study is the first to investigate the molecular basis of hypermetabolic tumor lesions in glioblastoma using precise three-dimensional biopsy isolation, whole genome/exome, and mRNA sequencing. These findings have diagnostic significance, provide insights into therapeutic resistance, and shed light on the obstacles encountered by precision therapeutics for glioblastoma.

cancer biology↗

bioRxiv2021

Beta2-adrenoceptor agonist salbutamol increases leg glucose uptake and metabolic rate but not muscle glycogen resynthesis in recovery from resistance exercise of the quadriceps in lean young men

ContentBeta2-agonists evoke potent acute increases in peripheral glucose uptake and energy expenditure at rest. Exercise has been shown to blunt these effects. Whether this attenuation is extended into recovery from exercise is unknown. ObjectiveTo examine the effect of beta2-agonists on leg glucose uptake and leg metabolic rate in recovery from exercise. DesignIn a randomized, placebo-controlled, cross-over study using arteriovenous balance technique and analysis of thigh muscle biopsies we investigated the effect of 24mg oral salbutamol (a selective beta2-agonist) on leg glucose, oxygen, and lactate at rest, during exercise, and in recovery, as well as on muscle glycogen resynthesis. ParticipantsHealthy, lean, young men (n=12). ResultsLeg glucose uptake tended to be two-fold higher at rest (0.22{+/-}0.12mmol/min, P=0.06). Accumulated leg glucose uptake was higher in recovery (21.1{+/-}6mmol, P=0.018) with salbutamol, but not during exercise. Leg oxygen uptake was 80% greater at rest (11{+/-}2.1mmol/min, P<0.01). Accumulated leg oxygen uptake was higher in recovery (1755{+/-}348mL, P<0.01) with salbutamol, but not during exercise. Muscle glycogen was lower with salbutamol 0.5h (109{+/-}25mmol/mg dry-weight, P<0.01) and 5h (101{+/-}19mmol/mg dry-weight, P<0.01) into recovery, suggestive of augmented glycogen utilization during exercise. There was no difference in glycogen resynthesis or glycogen synthase activity in the 5-hour recovery period with salbutamol. ConclusionsThese findings suggest that while resistance exercise confounds the augmentation of leg glucose uptake and metabolic rate induced by beta2-agonist at rest, this suppression is not conserved into recovery from exercise.

physiology↗

bioRxiv2021

High-Intensity Interval Training Remodels the Proteome and Acetylome of Human Skeletal Muscle

Exercise is an effective strategy in the prevention and treatment of metabolic diseases. Alterations in the skeletal muscle proteome, including post-translational modifications, regulate its metabolic adaptations to exercise. Here, we examined the effect of high-intensity interval training (HIIT) on the proteome and acetylome of human skeletal muscle, revealing the response of 3168 proteins and 1263 lysine acetyl-sites on 464 acetylated proteins. We identified global protein adaptations to exercise training involved in metabolism, excitation-contraction coupling, and myofibrillar calcium sensitivity. Furthermore, HIIT increased the acetylation of mitochondrial proteins, particularly those of complex V. We also highlight the regulation of exercise-responsive histone acetyl-sites. These data demonstrate the plasticity of the skeletal muscle proteome and acetylome, providing insight into the regulation of contractile, metabolic and transcriptional processes within skeletal muscle. Herein, we provide a substantial hypothesis-generating resource to stimulate further mechanistic research investigating how exercise improves metabolic health. Impact statementHostrup and colleagues identify global proteomic and acetylomic adaptations to high-intensity interval training, demonstrating adaptations to processes regulating metabolism and contraction.

physiology↗

bioRxiv2019

MS Atlas - A molecular map of brain lesion stages in progressive multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disorder of the central nervous system with an untreatable late progressive phase in a high percentage of patients. Molecular maps of different stages of brain lesion evolution in patients with progressive MS (PMS) are missing but critical for understanding disease development and to identify novel targets to halt progression. We introduce the first MS brain lesion atlas (msatlas.dk), developed to address the current challenges of understanding mechanisms driving the fate of PMS on lesion basis. The MS Atlas gives means for testing research hypotheses, validating candidate biomarkers and drug targets. The MS Atlas data base comprises comprehensive high-quality transcriptomic profiles of 73 brain white matter lesions at different stages of lesion evolution from 10 PMS patients and 25 control white matter samples from five patients with non-neurological disease. The MS Atlas was assembled from next generation RNA sequencing of post mortem samples using strict, conservative preprocessing as well as advanced statistical data analysis. It comes with a user-friendly web interface, which allows for querying and interactively analyzing the PMS lesion evolution. It fosters bioinformatics methods for de novo network enrichment to extract mechanistic markers for specific lesion types and pathway-based lesion type comparison. We describe examples of how the MS Atlas can be used to extract systems medicine signatures. We also demonstrate how its interface can interactively condense and visualize the atlas content. This compendium of mechanistic PMS white matter lesion profiles is an invaluable resource to fuel future multiple sclerosis research and a new basis for treatment development.

systems biology↗

bioRxiv2017

Diet And Life Stage Associated Remodeling Of Lipid Metabolism Regulation In The Duplicated Atlantic Salmon Genome

Atlantic salmon migrates from rivers to sea to feed, grow and develop gonads before returning to spawn in freshwater. These habitat shifts require great phenotypic plasticity. To address the unresolved question of how the shift in diet between fresh and saltwater affects the regulation of metabolic function, we fed salmon contrasting diets in each of the two life stages. Combining transcriptomics with comparative genomics, we found that lipid metabolism undergoes a concerted shift between fresh- and saltwater stages. Lipogenesis and lipid transport become less active in liver after transition to saltwater, while genes for lipid uptake in gut are more expressed in lipid-rich seawater environments. We assess how the whole-genome duplication that gave rise to the salmonids has impacted the evolution of lipid metabolism, and find signatures of pathway-specific selection pressure on gene duplicates, as well as a limited number of cases of increased gene dosage.

evolutionary biology↗