Biology subjects

Richter, E.

Publications and source records attributed to Richter, E..

6 recordsLinked to original sources

bioRxiv2026

Rac1 deficiency reduces mitochondrial respiratory capacity, impairs fatty acid metabolism and causes muscle wasting

BackgroundThe age-related progressive decline in skeletal muscle function is characterised by declining mitochondrial quality control and perturbed fatty acid metabolism, contributing to frailty and increased mortality. The actin cytoskeleton, a key structural component of skeletal muscle, has recently been implicated in mitochondrial anchoring and dynamics. However, the role of actin-regulating proteins, including the Rho GTPase Rac1, in mitochondrial function and age-associated metabolic and functional muscle deterioration remains undefined. MethodsSkeletal muscle from mice with inducible muscle-specific deletion of Rac1 (Rac1 imKO) underwent unbiased mass spectrometry-based proteomic profiling. Mitochondrial morphology was assessed by transmission electron microscopy, and physiological parameters, including muscle mass and contraction-stimulated palmitate oxidation in isolated soleus muscle, were evaluated. Mitochondrial respiratory function was determined by high-resolution respirometry in permeabilised gastrocnemius skeletal muscle fibre bundles. Biochemically, muscular triacylglycerol (TG) content, mRNA (qPCR) and protein (immunoblotting) content were determined. In vastus lateralis muscle biopsies from healthy, untrained young (20-30 years) and old, sarcopenic (83-94 years) men, Rac1 and mitochondrial respiratory protein abundances were measured. A complementary human genetic association analysis was performed using the FinnGen dataset. ResultsRac1 deficiency triggered muscle wasting in middle-aged mice (Gastrocnemius: -10%; Quadriceps: -7%). Preceding muscle wasting, gene set enrichment analysis identified enrichment in fatty acid metabolism and oxidative phosphorylation pathways, consistent with increased mitochondrial volume density in Rac1 imKO muscle (subsarcolemmal: +467%; intermyofibrillar: +166%). Despite mitochondrial expansion at this stage, Rac1 deficiency attenuated the increase in palmitate oxidation in response to muscle contraction (-62%). At the muscle-wasting stage, Rac1 imKO muscle exhibited reduced mitochondrial respiratory capacity (-25-32%). Additionally, the mitochondrial dysfunction was associated with an accumulation of muscle TG (+78%, p = 0.096) and upregulation of fatty acid transporter, CD36 protein content (+25%), indicative of altered fatty acid handling. In humans, Rac1 muscle protein content was increased in old, sarcopenic subjects compared to young (+41%), and negatively correlated with quadriceps cross-sectional area (CSA) (r = -0.475) and type II fibre CSA (r = -0.466). In old, sarcopenic muscle, Rac1 protein content correlated negatively with protein content of multiple mitochondrial respiratory complexes (CI: r = -0.690, CIV: r = -0.938, CV: r = -0.704). GWAS further identified associations between Rac1 SNP variants and lipid metabolic and muscle-wasting diseases. ConclusionsMuscle Rac1 deficiency reduces mitochondrial respiratory capacity and metabolic flexibility through impaired fatty acid metabolism, leading to muscle wasting and highlighting a potential therapeutic target in age-related functional decline.

Molecular Biology↗

bioRxiv2026

Plasma proteomics identifies an IL-6–associated SAA axis linked to muscle wasting in patients with cancer cachexia

Nearly half of patients with advanced lung cancer develop cachexia, a debilitating syndrome that worsens prognosis. We conducted longitudinal clinical and plasma proteomic profiling of 67 patients with non-small cell lung cancer, with and without cachexia, during first-line treatment. Patients with cachexia at diagnosis exhibited elevated risk of hospitalization and treatment-delaying toxicity. At diagnosis, 128 plasma proteins were upregulated and 67 downregulated in cachectic relative to non-cachectic patients. Longitudinal assessments of body composition, physical performance, metabolism, clinical outcomes, and nutritional risk revealed distinct fat and muscle wasting phenotype trajectories. 71 proteins were associated with fat loss, 92 with muscle loss, and 177 with concurrent muscle and weight loss. We identified and functionally validated 8 plasma proteins linked to muscle loss and adverse clinical outcomes. In a separate cohort of 147 patients with advanced pancreatic cancer receiving the interleukin-6 (IL-6) inhibitor tocilizumab, pharmacological suppression of serum amyloid A (SAA) levels following IL-6 inhibition suggests a systemic IL-6-SAA axis. These results collectively highlight SAA1 and SAA2 as IL-6-driven, cachexia-associated factors that reduce human myotube width. These findings uncover new potential therapeutic targets for cachexia.

Systems Biology↗

bioRxiv2025

Fast and Easy Whole-Brain Network Model Parameter Estimation with Automatic Differentiation

Personalized brain modeling at clinically relevant scales requires integrating biophysical models with empirical neuroimaging data, yet high-dimensional parameter estimation in whole-brain network models remains computationally prohibitive. We present TVB-Optim, an open-source Python library providing a general and extensible framework for gradient-based optimization of brain network models build on JAX. Leveraging automatic differentiation, we demonstrate direct optimization of thousands of parameters, from global coupling (N=2) to regional dynamics (N=168) to full structural connectivity matrices (N=14,028), across functional MRI and magnetoencephalography data. Forward simulations achieve 10x CPU speedup over reference implementations and scale efficiently to GPU and multi-device configurations. We establish best practices through documented workflows that combine coarse parameter space exploration with gradient refinement, often yielding superior solutions faster than gradient methods alone. By bridging mechanistic neuroscience with modern machine learning infrastructure, TVB-Optim enables large-scale personalized brain models, bringing computational neuroscience closer to clinical translation.

neuroscience↗

bioRxiv2025

Sex Differences in Plasma Levels of Endocannabinoids and Related Lipids Before and After acute and repeated mTBI: an exploratory study for plasma biomarkers for mTBI

Mild traumatic brain injury (mTBI) is common diagnosis across all age groups and while most symptoms resolve within a few weeks; between 10 and 25 percent of mTBI patients suffer long-term problems. Known as post-concussion syndrome (PCS), symptoms include headache, a range of cognitive deficits, and depression. Currently, there are no established treatments for PCS and no clear predictive biometrics to determine which patients are at increased risk. Previous studies have identified some protein-derived plasma biomarkers for mTBI, however, the effects of mTBI on lipid signaling molecules and metabolites in blood is largely unknown. Endogenous lipids (endolipids) such as the endocannabinoids (eCBs) and their congeners are lipid signaling molecules that are associated with promoting neuroprotective responses after head trauma in animal models. Here, we examine the plasma lipidome using a rat model of acute and repeated mTBI that we previously demonstrated had a sex dependent change in neuroinflammation wherein females showed a higher degree of neurodegeneration after repeated head-injury than males. Key results of this exploratory lipidomics screen here demonstrates that acute head injury drives significantly more changes in plasma endolipids in males (32%) than females (8%), whereas, on the second day of head injury, only 11% change in males but 15% in females. Some key endolipids were modified in both males are precursors for resolving molecules and this was lacking in females. Given that females with repeated mTBI in this model demonstrated aspects of PCS, this could be an important component in evaluating clinical cases. Endolipids in the screen were measurable in plasma using only 100{micro}L, a volume necessary to be able to perform multiple blood draws on these rodent subjects. This threshold provides evidence that the levels of these endolipids could be readily measured throughout a patients recovery. Therefore, this family of endolipids has the potential to provide data on the progression of the injury and could be another crucial aspect in predicting mTBI outcomes.

neuroscience↗

bioRxiv2023

Pantothenate Kinase 4 controls efficient skeletal muscle energy substrate metabolism via acetyl-CoA

Metabolic inflexibility in skeletal muscle (SkM) is closely linked to metabolic diseases. Exercise improves metabolic flexibility, rendering it a valuable discovery tool of mechanisms promoting efficient metabolism of glucose and lipids. We herein discover pantothenate kinase 4 (PanK4) as a conserved exercise target with high abundance in SkM. We go on to show that murine muscle Pank4 is dysregulated with high-fat diet feeding, and identify human PANK4 variants that associate with glycemic control and body mass index traits, indicating important roles of PanK4 in glucose metabolism and growth. Consistent with the latter, germline deletion of PanK4 reduces circulating IGF-1 and stunts growth in mice. Deletion specifically in mouse SkM reveals that PanK4 facilitates fatty acid oxidation by acting as a regulator of SkM acetyl-CoA, a key node in metabolism of both glucose and lipids. Consequently, without PanK4, elevated SkM acetyl-CoA levels allosterically gridlock key enzymes required for efficient lipid and glucose utilization, and these SkM metabolic perturbations manifest in whole-body insulin resistance. As proof of principle, we show that an increase in muscle PanK4 lowers SkM acetyl-CoA and increases SkM glucose utilization. Our findings identify PanK4 as a novel regulator of SkM energy substrate metabolism, warranting inclusion in comprehensive strategies against metabolic disease.

physiology↗

bioRxiv2020

Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. Here, we report that low plasma interleukin-3 (IL-3) levels were associated with increased severity and mortality during SARS-CoV-2 infections. IL-3 promoted the recruitment of antiviral circulating plasmacytoid dendritic cells (pDCs) into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells. This study identifies IL-3 as a predictive disease marker and potential therapeutic target for SARS-CoV-2 infections.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗