Biology subjects

Sotak, M.

Publications and source records attributed to Sotak, M..

3 recordsLinked to original sources

bioRxiv2026

Dynamic Responses to an Inflammatory Challenge Distinguish Metabolic Health Across Lean and Obese Individuals

Inflammation is a key driver of cardiometabolic disease, yet it remains unclear whether systemic inflammatory markers can distinguish metabolically healthy from unhealthy individuals or capture the temporal dynamics of inflammation. Here, we combined systemic immune profiling with a cantharidin-induced peripheral blister model to investigate dynamic inflammatory regulation across metabolic phenotypes in metabolically healthy lean (MHL), metabolically unhealthy lean (MUL), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO) individuals. While systemic inflammation was elevated in obesity, differences between metabolically healthy and unhealthy groups were modest, with limited discrimination by plasma proteomics, circulating leukocyte phenotyping, and whole-blood transcriptomics. In contrast, the dynamic response to inflammatory challenge revealed pronounced differences at proteomic, cellular, and transcriptomic levels. Metabolically unhealthy individuals exhibited exaggerated early innate immune responses, impaired inflammatory resolution and tissue repair, reduced recruitment of reparative immune cells, and sustained T cell presence. Transcriptomic analyses further showed blunted dynamic gene regulation and defective epidermal barrier restoration. These findings indicate that metabolic health is better reflected in tissue-level inflammatory dynamics than in systemic measures.

immunology↗

bioRxiv2026

Lipoxins Regulate Intercalated Disk-Associated Signaling and Immune Remodeling in Dilated Cardiomyopathy

We investigated whether pro-resolving lipid mediators of the lipoxin family can attenuate fibrosis and inflammation in muscle LIM protein knockout (MLPko) mice, a model of dilated cardiomyopathy (DCM). Male and female MLPko mice received either vehicle or a mix of lipoxin-A4 and lipoxin-B4 three times per week for six weeks. Cardiac function was assessed using echocardiography, and fibrosis and DCM-associated cardiac signaling was evaluated through histology, immunofluorescence and immunoblot analyses. Flow cytometry and RNA sequencing (RNAseq) was performed to identify changes in cardiac gene expression and characterize macrophage subpopulations, respectively. Flow cytometry showed increased inflammatory CD11c+ M1-like macrophages and reduction of CD206+ M2-like macrophages in MLPko hearts compared to wild-type controls. Lipoxin treatment partially reversed the macrophage imbalance and showed mild improvements in cardiac physiology in MLPko males. RNAseq analyses revealed sex-dependent alterations in the expression of pro-fibrotic and inflammation-related genes, suggesting changes in extracellular matrix (ECM) integrity and composition, and to the adaptive immune response. Intriguingly, several ECM proteins showed unexpected localizations at cardiac intercalated disks, which are known to be involved in DCM etiology. Further analysis identified lipoxin-dependent reduction in the DCM-associated expression of intercalated disk components only in lipoxin-treated MLPko males. Lipoxins also modulated key cardiac signaling pathways in a sex-specific manner, including Erk1/2 and PKC-linked Ankrd1/Carp1, which is associated with DCM development in MLPko mice. While lipoxins do not directly reverse cardiac dysfunction or fibrosis in MLPko mice, they may provide sex-specific protective effects by modulating DCM-related cardiac signaling pathways and by influencing immune-cell populations.

cell biology↗

bioRxiv2022

Combined loss of obscurin and obscurin-like 1 in murine hearts results in impaired diastolic dysfunction, altered metabolism and deregulated mitophagy.

Muscle proteins of the obscurin protein family play important roles in sarcomere organization, sarcoplasmic reticulum (SR) and T-tubule architecture and function. However, their precise molecular functions and redundancies between protein family members as well as their involvement in cardiac diseases remain to be fully understood. To investigate the functional roles of obscurin and its close homologue obscurin-like 1 (Obsl1) in the heart, we generated and analyzed knockout mice for obscurin, Obsl1, as well as obscurin/Obsl1 double-knockouts (dKO). We show that dKO mice are viable but show postnatal deficits in cardiac muscle SR and mitochondrial architecture and function at the microscopic, biochemical and cellular level. Altered SR structure resulted in perturbed calcium cycling, while mitochondrial ultrastructure deficits were linked to decreased levels of Chchd3, a Micos complex protein. Hearts of dKO mice also show increased expression of Atg4d, a novel Obsl1 interacting protein, resulting in abnormal mitophagy and increased unfolded protein response. At the physiological level, loss of obscurin and Obsl1 resulted in a profound delay of cardiac relaxation, associated with metabolic signs of heart failure. Taken together, our data suggest that obscurin and Obsl1 play crucial roles in cardiac SR structure, calcium cycling, mitochondrial function, turnover and metabolism.

cell biology↗