Biology subjects

Ullrich, M.

Publications and source records attributed to Ullrich, M..

4 recordsLinked to original sources

bioRxiv2025

Repeated Disuse Atrophy Imprints a Molecular Memory in Skeletal Muscle: Transcriptional Resilience in Young Adults and Susceptibility in Aged Muscle

Disuse-induced muscle atrophy is common after illness, injury, or falls and becomes increasingly frequent with ageing. Whether skeletal muscle retains a "memory" of repeated disuse remains unknown. We investigated repeated lower-limb immobilization in young adults and a refined aged rat model, integrating physiological, multi-omic, immunohistochemical, biochemical, and primary human muscle stem cell (MuSC) analyses. To enable robust age comparisons, we integrated published young rat data with newly generated aged rat data. In young human muscle, repeated disuse elicited attenuated transcriptional perturbations in oxidative and mitochondrial pathways, suggestive of a protective molecular memory, despite similar atrophy to initial disuse. In contrast, aged muscle exhibited a detrimental memory, characterised by greater atrophy, exaggerated suppression of aerobic metabolism genes despite recovery after initial disuse, NAD and mitochondrial DNA depletion, and activation of proteasomal, extracellular-matrix, and DNA-damage pathways. Whereas young rats recovered muscle mass after initial disuse, aged rats did not. Repeated disuse induced DNA hypermethylation and downregulation of aerobic metabolism and mitochondrial genes across species. NR4A1 remained suppressed into recovery, while AChR subunit genes (CHRNA1, CHRND) were epigenetically primed. NMRK2, an NAD biosynthesis gene, was among the most downregulated after both atrophy periods, and nicotinamide riboside improved myotube size in MuSCs post-atrophy. Repeated disuse atrophy imprints a molecular memory in skeletal muscle shaping transcriptional resilience in young adults and exaggerated susceptibility in aged muscle.

physiology↗

bioRxiv2025

Alcohol consumption drives sex- and region- specific disruption of somatostatin signaling in mice

The prefrontal cortex (PFC), which is thought to be disrupted early in the cycle of substance use and addiction [1], is comprised of a complex microcircuit of long-range glutamatergic pyramidal neurons controlled by GABAergic-expressing local inhibitory neurons [2, 3]. Somatostatin (SST)-expressing neurons are a subpopulation of these local GABAergic inhibitory cells and provide both peptidergic and GABAergic control over these PFC circuits [3, 4], and are disturbed following alcohol consumption in humans [5] and in rodent models [6, 7]. However, little is known about how endogenous SST peptide signaling is affected by alcohol. Using ex vivo electrophysiology, immunohistochemistry, in situ hybridization, and behavior, we demonstrate robust down-regulation of SST control over pyramidal output activity in the prelimbic (PL), but not infralimbic (IL), PFC after alcohol exposure. We also show this is likely mediated by changes in SST receptor expression levels and not disrupted expression or capacity for release of SST peptide, suggesting postsynaptic homeostatic changes to SST signaling following binge alcohol consumption in mice that may underlie post-alcohol dysregulation in mood. This provides insight into how voluntary alcohol consumption disrupts PFC peptide signaling and suggests a potential therapeutic target for the treatment of alcohol use disorder (AUD).

neuroscience↗

bioRxiv2024

DJ-1 mediates regulation of metabolism and immune response in Parkinsons disease astrocytes and Glioblastoma cells

An inverse correlation for the expression of Parkinsons disease (PD)- and cancer-associated genes has been previously reported. Genes that are upregulated in cancer are frequently downregulated in PD and vice versa. PARK7, encoding DJ-1, was initially identified as an oncogene, but loss of DJ-1 causes early-onset PD. However, it remains elusive how differential DJ-1 levels contribute to opposite cell fates in cancer and PD. Here, we demonstrate specific effects of differential DJ-1 protein levels on the energy metabolism and cell growth in patient-derived cellular models of PD and glioblastoma (GBM) cell lines. Impaired energy metabolism was associated with an increased immune response upon IL-1{beta} stimulation and increased apoptosis and decreased cell growth in models of PD, whereas in GBM cells increased metabolic activity translated into a reduced immune response and increased cell growth. Furthermore, we found decreased glutathione (GSH) synthesis and therefore increased levels of reactive oxygen species (ROS) and oxidized glutathione (GSSG) in models of DJ-1 deficiency and decreased ROS levels in GBM cell lines. Thus, the mechanism by which DJ-1 modulates these phenotypes is the same in both diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/621212v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@4eccb4org.highwire.dtl.DTLVardef@161669corg.highwire.dtl.DTLVardef@197bfc3org.highwire.dtl.DTLVardef@1aecb36_HPS_FORMAT_FIGEXP M_FIG C_FIG DJ-1 levels modulate GSSG/GSH ratio and ROS levels, which results in divergent effects on cell growth and immune response in DJ-1-dependent glial pathologies in glioblastoma and PD. In models of PD, DJ-1 level dependent phenotypes can be rescued by antioxidant treatment that reduces the GSSG/GSH ratio and ROS levels.

neuroscience↗

bioRxiv2021

Jetlag Expectations, not Circadian Parameters, Predict Jetlag Symptom Severity in Travelers

After a flight across multiple time zones, most people show a transient state of circadian misalignment causing temporary malaise known as jetlag disorder. The severity of the elicited symptoms is postulated to depend mostly on circadian factors such as the number of time zones crossed and the direction of travel. Here, we examined the influence of prior expectation on symptom severity, compared to said "classic" determinants, in order to gauge potential psychosocial effects in jetlag disorder. To this end, we monitored jetlag symptoms in travel-inexperienced individuals (n=90, 18-37y) via detailed questionnaires twice daily for one week before and after flights crossing >3 time zones. We found pronounced differences in individual symptom load that could be grouped into 4 basic symptom trajectories. Both traditional and newly devised metrics of jetlag symptom intensity and duration (accounting for individual symptom trajectories) recapitulated previous results of jetlag prevalence at about 50-60% as well as general symptom dynamics. Surprisingly, however, regression models showed very low predictive power for any of the jetlag outcomes. The classic circadian determinants, including number of time zones crossed and direction of travel, exhibited little to no link with jetlag symptom intensity and duration. Only expectation emerged as a parameter with systematic, albeit small, predictive value. These results suggest expectation as a relevant factor in jetlag experience - hinting at potential placebo effects and new treatment options. Our findings also caution against jetlag recommendations based on circadian principles but insufficient evidence linking circadian re-synchronization dynamics with ensuing symptom intensity and duration. Significance StatementJetlag disorder afflicts millions of travelers each year - a nuisance on holiday trips but also a danger in safety and performance-critical operations. For effective prevention and treatment, it is critical to understand what influences jetlag severity, i.e. jetlag symptom intensity and duration. In contrast to what guidelines state, in our study, we did not find that symptom severity could be explained by the number of time zones crossed or travel direction. Rather, travelers expectations about how long and strongly they will suffer from jetlag symptoms was the only factor systematically predicting jetlag severity. If this holds true not only for subjective but also objective symptoms, we need to revisit assumptions about how circadian desynchronization relates to experienced jetlag symptoms.

neuroscience↗