Biology subjects

Ryden, M.

Publications and source records attributed to Ryden, M..

7 recordsLinked to original sources

bioRxiv2025

Transcriptomic Profiling of scWAT Reveals Reduced Lipid-Associated Macrophage Signatures in Long-Term Endurance- and Resistance-Trained Athletes

Regular exercise training is associated with systemic and tissue-specific performance and health benefits, yet long-term molecular adaptations in subcutaneous abdominal white adipose tissue (scWAT) remain unclear. We analyzed the resting scWAT transcriptome of 89 adults (35-50 years) who were long-term (>15 years) endurance- or strength-trained, or untrained. Long-term training was linked to enrichment of ribosomal, mitochondrial, and aerobic metabolism-related pathways, while immune-related pathways were enriched in untrained individuals. A distinct sex dimorphic scWAT was identified: untrained females exhibited a more metabolically favorable, trained-like transcriptomic profile, and untrained males an untrained-like profile. In trained males, the inflammatory gene signature was lower than in untrained males. We also identified 11 genes specific to lipid-associated macrophages with lower expression in trained individuals, particularly in all endurance-trained individuals and strength-trained females. These findings highlight sex-specific, exercise-induced adaptations in scWAT relevant to metabolic health, and underscore the importance of including both sexes in scWAT research.

physiology↗

bioRxiv2024

Defining the Vascular Niche of Human Adipose Tissue Across Metabolic Conditions

IntroductionAdipose tissue homeostasis depends on a healthy vascular network. Vascular malfunction is a hallmark of obesity1, and vascular endothelial dysfunction, in particular, accelerates metabolic diseases, including obesity and diabetes. Single-cell transcriptomics studies have mapped the cellular landscape of human white adipose tissue (WAT)2-8. However, the vascular niche remains relatively undefined9, especially regarding its heterogeneity, function, and role in metabolic disease. To address this gap, we created a single-cell transcriptome atlas of human subcutaneous adipose tissue (SAT), comprising nearly 70,000 vascular cells from 65 individuals. We characterized seven canonical adipose tissue endothelial cell (AdEC) subtypes and identified a distinct heterogenous population, here referred to as sub-AdECs. Sub-AdECs exhibit gene signatures characteristic of multiple cell types, including mesenchymal, adipocytic, and immune, suggesting they possess diverse properties and identities. Through computational analyses and whole-mount imaging, we validated the occurrence of sub-AdECs and show that these cells likely arise through endothelial-mesenchymal transition (EndMT), the modulation of which limits obesity-associated adipose tissue inflammation and fibrosis. Furthermore, we compared the transcriptomes of vascular cells from individuals living with or without obesity and type 2 diabetes and find metabolic disease-associated inflammatory and fibrotic transcriptomic patterns. The atlas and accompanying analyses establish a solid foundation for investigations into the biology of the adipose tissue vascular niche and its contribution to the pathogenesis of metabolic disease.

cell biology↗

bioRxiv2024

Personalized Molecular Signatures of Insulin Resistance and Type 2 Diabetes

HighlightsO_LIAdvanced proteomics analysis reveals personalized signatures of insulin resistance C_LIO_LIFasting muscle proteome and phosphoproteome predicts whole-body insulin sensitivity C_LIO_LIInsulin-stimulated phosphoproteome reveals selective insulin resistance signatures C_LIO_LIPhosphoproteome and proteome atlas explains sex-specific muscle metabolism C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/578994v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@a83000org.highwire.dtl.DTLVardef@1e77336org.highwire.dtl.DTLVardef@3d1ecdorg.highwire.dtl.DTLVardef@b1592b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG Insulin resistance is a hallmark of type 2 diabetes, which is a highly heterogeneous disease with diverse pathology. Understanding the molecular signatures of insulin resistance and its association with individual phenotypic traits is crucial for advancing precision medicine in type 2 diabetes. Utilizing cutting-edge proteomics technology, we mapped the proteome and phosphoproteome of skeletal muscle from >120 men and women with normal glucose tolerance or type 2 diabetes, with varying degrees of insulin sensitivity. Leveraging deep in vivo phenotyping, we reveal that fasting proteome and phosphoproteome signatures strongly predict insulin sensitivity. Furthermore, the insulin-stimulated phosphoproteome revealed both dysregulated and preserved signaling nodes - even in individuals with severe insulin resistance. While substantial sex-specific differences in the proteome and phosphoproteome were identified, molecular signatures of insulin resistance remained largely similar between men and women. These findings underscore the need for precision medicine approaches in type 2 diabetes care, acknowledging disease heterogeneity.

biochemistry↗

bioRxiv2024

Decreased sarcomeric mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin action in type 2 diabetes

Plasma creatine levels are associated with risk of type 2 diabetes. Since skeletal muscle is the main disposal site of both creatine and glucose, we investigated the role of intramuscular creatine metabolism in the pathophysiology of insulin resistance in type 2 diabetes. We report in men with type 2 diabetes, plasma creatine levels are increased, while intramuscular phosphocreatine content is reduced. These alterations are coupled to reduced expression of sarcomeric mitochondrial creatine kinase 2 (CKMT2). In C2C12 myotubes, Ckmt2 silencing reduced mitochondrial respiration, membrane potential, and glucose oxidation. Electroporation-mediated overexpression of Ckmt2 in skeletal muscle of high-fat diet-fed male mice increased mitochondrial respiration, independent of creatine availability. Thus, beyond the canonical role of CKMT2 on creatine phosphorylation, we reveal a previously underappreciated role of CKMT2 on mitochondrial homeostasis, independent of insulin action. Collectively, our data provides functional evidence into how CKMT2 mediates mitochondrial dysfunction associated with type 2 diabetes.

physiology↗

bioRxiv2023

A Spatiotemporal Proteomic Map of Human Adipogenesis

White adipocytes function as the major energy reservoir in humans by storing substantial amounts of triglycerides and their dysfunction is associated with metabolic disorders. However, the mechanisms underlying cellular specialization during adipogenesis remain unknown. Here, using a high-sensitivity-high throughput workflow, we generated a spatiotemporal proteomic atlas of human adipogenesis encompassing information for ~8.000 proteins. Our systematic approach gives insights into cellular remodeling and the spatial reorganization of metabolic pathways to optimize cells for lipid accumulation and highlights the coordinated regulation of protein localization and abundance during adipogenesis. More specifically, we identified a compartment-specific regulation of protein levels and localization changes of metabolic enzymes to reprogram branched chain amino acid and one-carbon metabolism to provide building blocks and reduction equivalents for lipid synthesis. Additionally, we identified C19orf12 as a differentiation induced and adipocyte-specific lipid droplet (LD) protein, which interacts with the translocase of the outer membrane (TOM) complex of LD associated mitochondria and regulates adipocyte lipid storage. Overall, our study provides a comprehensive resource for understanding human adipogenesis and for future discoveries in the field. KEY POINTSO_LIHuman adipogenesis induces distinct temporal changes in protein abundance C_LIO_LI20% of all detected proteins change organellar localization during adipogenesis C_LIO_LIBCAA and one-carbon metabolism enzyme levels and localizations are coordinately regulated to promote adipogenesis C_LIO_LIC19orf12 is an adipocyte specific LD protein and regulator of lipid storage C_LI

molecular biology↗

bioRxiv2021

Disrupted circadian core-clock oscillations in Type 2 Diabetes are linked to altered rhythmic mitochondrial metabolism

Circadian rhythms are generated by an auto-regulatory feedback loop composed of transcriptional activators and repressors. Disruption of circadian rhythms contributes to Type 2 diabetes (T2D) pathogenesis. We elucidated whether altered circadian rhythmicity of clock genes is associated with metabolic dysfunction in T2D. Transcriptional cycling of core clock genes ARNTL, CLOCK, CRY1 and NR1D1 was altered in skeletal muscle from individuals with T2D and this was coupled with reduced number and amplitude of cycling genes and disturbed circadian oxygen consumption. Mitochondrial associated genes were enriched for differential circadian amplitudes in T2D, and positively correlated with insulin sensitivity. ChIP- sequencing identified CLOCK and BMAL1 binding to circadian mitochondrial genes associated with insulin sensitivity, implicating regulation by the core clock. Mitochondria disruption altered core-clock gene expression and free-radical production, phenomena that were restored by resveratrol treatment. We identify bi-directional communication between mitochondrial function and rhythmic gene expression, processes which are disturbed in diabetes.

physiology↗

bioRxiv2021

Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease

Preadipocytes are crucial for healthy adipose tissue expansion. Preadipocyte differentiation is altered in obese individuals, which has been proposed to contribute to obesity-associated metabolic disturbances. Here, we demonstrate that impaired alternative splicing and dysregulated endoplasmic reticulum (ER)- associated protein degradation (ERAD) represent marker pathways of dysfunctional preadipocytes in obese individuals with insulin resistance (IR)/type 2 diabetes (T2D). Down-regulation of a key member of the major spliceosome, PRFP8/PRP8, as observed in IR/T2D preadipocytes from subcutaneous (SC) fat, prevented adipogenesis by altering both the expression and splicing patterns of adipogenic transcription factors and lipid droplet-related proteins, while adipocyte differentiation was restored upon recovery of PRFP8/PRP8 normal levels. Adipocyte differentiation was also compromised under conditions of ERAD hyperactivation, as occurs in SC and omental (OM) preadipocytes in IR/T2D obesity. Thus, targeting mRNA splicing and ER proteostasis in preadipocytes could improve adipose tissue function and thus contribute to metabolic health in obese individuals.

cell biology↗