Biology subjects

Frank, E.

Publications and source records attributed to Frank, E..

12 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↗

bioRxiv2026

Scouting ecological drivers of natural enemies in citrus orchards: implications for biological control in the Corsican agricultural landscape

O_LIEffective pest control requires a better understanding of natural enemy ecology, particularly how their distribution responds to landscape structure and local management. Agricultural intensification has simplified landscapes, reducing biodiversity and constraining pest control. Landscape-scale surveys are therefore needed to identify strategies that support natural enemies in agricultural systems. C_LIO_LIFrom 2021 to 2022, over three seasons, we surveyed 25 clementine orchards across a gradient of landscape complexity in Corsica. We modelled the tree-level occurrence of four natural enemy species in relation to ecological context across multiple spatial and temporal scales. Site-level evenness, reflecting differences in species occurrence frequencies, was also estimated to assess how natural enemy assemblages vary across local management and landscape gradients. C_LIO_LIClimate and local management were the primary drivers of species occurrence, with additional contributions from landscape factors. Species displayed distinct responses, while model performance increased with the number of sampled trees, plateauing at around half of the sampling effort. C_LIO_LISite-level evenness was higher in organic orchards than in conventional orchards. In conventional orchards, it responded to landscape structure in a scale-dependent manner, increasing at the larger scale with the heterogeneity and spatial continuity of semi-natural habitats. C_LIO_LISynthesis and applications. Organic farming enhances natural enemy presence and diversity in Corsican citrus orchards, while the naturalness and complexity of surrounding landscape can mitigate species scarcity in conventional orchards. We recommend continued long-term monitoring of arthropod communities in these systems, prioritizing the number of sampling sites and years while reducing the number of trees sampled per site to optimize effort. C_LI

ecology↗

bioRxiv2026

Decreased food intake contributes to elevated insulin-responsiveness in pre-clinical cancer cachexia

PurposeCancer cachexia is a life-threatening complication of advanced malignancies, driven by anorexia and profound systemic metabolic reprogramming. Insulin action in skeletal muscle is markedly impaired in patients with cancer and may contribute directly to cachexia pathogenesis. However, the interplay between reduced nutrient intake and cancer-associated metabolic rewiring in cachexia remains poorly defined. Clarifying this relationship is essential for identifying the fundamental drivers of cachexia and for developing effective therapeutic strategies. MethodsWe assessed metabolic rewiring by glucose tolerance test and isotopic tracers to determine muscle insulin-stimulated glucose uptake in male cachectic and non-cachectic C26- and KPC-tumor-bearing, as well as mice towards C26 cachectic mice. ResultsCachectic C26-tumor-bearing mice displayed reduced body weight, lean, and fat mass, and food intake (-20%, -15%, -75%, -40%, respectively). Cachectic C26- and KPC-tumor mice showed improved glucose tolerance compared to non-cachectic mice, correlating inversely with tumor size. Ex vivo insulin-stimulated glucose uptake was elevated in soleus (+78%) and extensor digitorum longus (+35%) muscle from cachectic C26-cancer mice compared to non-cachectic and control mice. This increase was associated with enhanced AKT signaling. This was phenocopied in pair-fed non-tumor-bearing mice to match the food intake of cachectic mice, where glucose tolerance, insulin-stimulated glucose uptake ex vivo, and AKT signaling were all enhanced by food restriction. ConclusionsOur findings suggest that enhanced skeletal muscle insulin responsiveness in cachectic tumor-bearing mice is due to anorexia-induced adaptations, highlighting AKT signaling as a key node connecting nutrient status to muscle glucose metabolism in cancer cachexia. HighlightsO_LIC26 and KPC cancer-induced weight loss (cachexia) increases glucose tolerance in mice C_LIO_LIInsulin responsiveness is increased in cachectic, but not in non-cachectic, tumor-bearing mice. C_LIO_LILowered food intake drives elevated muscle insulin responsiveness in cachectic mice C_LI

molecular biology↗

bioRxiv2025

Pathophysiological remodeling of the skeletal muscle microenvironment in patients with lung cancer

Background Muscle wasting, systemic inflammation, and functional decline are highly prevalent and detrimental in patients with advanced-stage non small cell lung cancer (NSCLC). Methods: In this cross sectional study, we investigated NSCLC associated muscle remodeling by analyzing skeletal muscle biopsies from patients with NSCLC (n = 18) and matched controls (n = 18) using quantitative proteomics, histology, fluorescence-activated cell sorting, gene expression profiling, and high resolution respirometry. Findings: NSCLC muscle was characterized by type II muscle fiber atrophy, greater collagen deposition, and redistribution of lipids to the extracellular matrix (ECM), together with remodeling of the inflammatory, immune, ECM and mitochondrial proteome. Additionally, mitochondrial respiratory capacity and morphology were altered in patients with NSCLC, which was associated with increased oxidative stress and dysregulated calcium handling. Concomitantly, we detected STAT3 activation and immune cell alterations, which may negatively impact skeletal muscle health in patients with NSCLC. Finally, we identified a shift in fibro-adipogenic progenitors (FAPs), favoring the CD90 subtype. Mechanistically, conditioned media from patient-derived FAPs reduced myotube width in vitro, uncovering a novel mechanism by which altered paracrine signaling from the muscle resident stromal compartment drives atrophy in cancer cachexia. Interpretation: These findings provide human evidence that altered FAP composition, mitochondrial homeostasis, calcium handling, and immune cell landscape accompany muscle wasting in NSCLC, which may inform therapeutic strategies to preserve skeletal muscle health in patients with cancer.

molecular biology↗

bioRxiv2024

Housing temperature dictates the systemic and tissue specific molecular responses to cancer in mice

Cancer cachexia is a metabolic condition affecting up to 80% of patients with cancer. Cachexia is mediated by reduced muscle and fat mass and impaired function, and it lowers survival for patients. With no approved drugs to treat cachexia, preclinical efforts focus on understanding the molecular mechanisms underlying this condition to reveal treatment targets. Housing laboratory mice at ambient temperature imposes cold stress, leading to induced thermogenic activity and consequent whole-body metabolic adaptations. Yet, the impact of housing temperature in in vivo preclinical cachexia remains unknown. We found that thermoneutral (TN) housing in C26 carcinoma-bearing (C26) mice affected lean and fat mass, but not muscle weight or force. TN housing improved glucose tolerance in C26 mice, while enhancing circulating abundance of FGF21 and IL-6. Thermogenic tissues, especially brown adipose tissue, exhibited housing temperature-dependent molecular responses to cancer in oxygen consumption, ATP levels and SERCA ATPase activity, which are all crucial for cancer-induced whole-body metabolic adaptations. We conclude that molecular and systemic adaptations to cancer in mice critically depend on housing temperature, which should be considered in the design and interpretation of preclinical cancer studies.

physiology↗

bioRxiv2024

Exploring the role of cultivar, year and plot age in the incidence of grapevine trunk diseases: insights from 20 years of regional surveys in France

Grapevine trunk diseases cause yield losses and vine mortality in vineyards worldwide. However, there have been few quantitative studies evaluating grapevine dieback on a large spatial and temporal scale. Here, we consolidated and standardized databases from the 13 main wine regions of France, compiling records of leaf symptoms associated with esca and Eutypa dieback from 2082 plots and 36 cultivars over a 20-year period. This large dataset was used (a) for quantitative analysis of the prevalence (number of plots with at least one symptomatic plant) and incidence (percentage of symptomatic plants) of esca and Eutypa dieback; and (b) to decipher the effects of cultivar, year and plot age on both the prevalence and incidence of esca leaf symptoms by temporal Bayesian modelling. Esca was present on a mean of 74 {+/-} 2% plots annually, with an incidence of 3.1 {+/-} 0.1%. Eutypa dieback occurred in 41 {+/-} 3% of the plots, with an incidence of 1.4 {+/-} 0.1%. Our modelling approach revealed that the cultivar had a significant impact on the prevalence of esca, but not on its incidence when prevalence is greater than zero. Esca prevalence remained stable, whereas esca incidence was higher than the mean value in six of the years after 2012. We also found a significant non-linear effect of plot age, with 10- to 30-year-old plots significantly more susceptible, depending on the cultivar. This study clearly illustrates the importance of considering extensive and continuous monitoring to improve our understanding of the impact and evolution of crop diseases.

plant biology↗

bioRxiv2023

The mitochondrial mRNA stabilizing protein, SLIRP, regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms

Summary and graphical abstractDecline in mitochondrial function associates with decreased muscle mass and strength in multiple conditions, including sarcopenia and type 2 diabetes. Optimal treatment could include improving mitochondrial function, however, there are limited and equivocal data regarding the molecular cues controlling muscle mitochondrial plasticity. Here we uncover the mitochondrial-mRNA-stabilizing protein SLIRP, in complex with LRPPRC, as a PGC-1 target that regulates mitochondrial structure, respiration, and mitochondrially-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracted mitochondrial defects induced by loss of LRPPRC/SLIRP, despite sustained low mitochondrially-encoded-mRNA pools, via increased mitoribosome translation capacity. In humans, exercise training robustly increased muscle SLIRP and LRPPRC protein content across exercise modalities and sexes, yet this increase was less prominent in subjects with type 2 diabetes. Our work identifies a mechanism of post-transcriptional mitochondrial regulation in skeletal muscle through mitochondrial mRNA stabilization. It emphasizes exercise as an effective approach to alleviate mitochondrial defects by possibly increasing mitoribosome capacity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/564600v2_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@1cdc6c5org.highwire.dtl.DTLVardef@b4cb1borg.highwire.dtl.DTLVardef@182871corg.highwire.dtl.DTLVardef@7462ea_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

The Rho GTPase Rac1 mediates exercise training adaptations

Exercise training elicits tremendous health benefits; however, the molecular underpinnings are poorly understood. As one of the most regulated groups of proteins following acute exercise in human muscle, Rho GTPases are unexplored candidates for mediating the beneficial effects of exercise. The Rho GTPase Rac1 was activated during multiple exercise modalities and remained elevated hours after resistance exercise in human muscle. Inducible muscle-specific Rac1 knockout (Rac1 imKO) mice, displayed attenuated muscle protein synthesis, glycogen resynthesis and p38 MAPK signaling in recovery from contractions. Exercise training upregulated Rac1 protein content in human and mouse muscle. Overexpression of hyperactive Rac1 elevated reactive oxidant species production during exercise yet did not induce a trained muscle phenotype. In Rac1 imKO mice, the improvements in running capacity and muscle mass after exercise training were diminished. Using gain- and loss-of-function mouse models and human muscle biopsies, we identify Rac1 as a regulator of exercise training adaptions. HighlightsO_LIVarious exercise modalities activate Rac1 signaling in human skeletal muscle. C_LIO_LIHSP27, MNK1, and CREB are Rac1-dependent contraction-responsive targets in muscle. C_LIO_LIPost-contraction protein synthesis requires Rac1 but not NOX2. C_LIO_LIRac1-NOX2 signaling is necessary for post-contraction glycogen resynthesis. C_LIO_LIExercise training increases Rac1 protein content in human and mouse muscles. C_LIO_LIRac1 mediates critical adaptations to exercise training. C_LI

molecular biology↗

bioRxiv2022

A-ring-fused pyrazoles of dihydrotestosterone targeting prostate cancer cells via the downregulation of the androgen receptor

High expression of the androgen receptor (AR) and the disruption of its regulation are strongly responsible for the development of prostate cancer (PCa). Therapeutically relevant non-steroidal or steroidal antiandrogens are able to block the AR effect by eliminating AR-mediated signalling. Herein we report the synthesis of novel steroidal pyrazoles derived from the natural sex hormone 5-dihydrotestosterone (DHT). 2-Ethylidene or 2-(hetero)arylidene derivatives of DHT obtained by regioselective Claisen-Schmidt condensation with acetaldehyde or (hetero)aromatic aldehydes in alkaline ethanol were reacted with monosubstituted hydrazines to give A-ring-fused 1,5-disubstituted pyrazoles as main or exclusive products, depending on the reaction conditions applied. Spontaneous or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-induced oxidation of the primarily formed pyrazolines resulted in the desired products in moderate to good yields, while 17-oxidation also occurred by using the Jones reagent as a strong oxidant. Transcriptional activity of the AR in a reporter cell line was examined for all novel compounds, and several previously synthesized similar DHT-based pyrazoles with differently substituted heteroring were also included to obtain information about the structure-activity relationship. Two specific regioisomeric groups of derivatives significantly diminished the transcriptional activity of AR in reporter cell line in 10 M concentration, and displayed reasonable antiproliferative activity in AR-positive PCa cell lines. Lead compound (3d) was found to be a potent AR antagonist (IC50 = 1.18 M), generally suppressed AR signalling in time and dose dependent manner, moreover, it also led to a sharp decrease in wt-AR protein level probably caused by proteasomal degradation. We confirmed the antiproliferative activity selective for AR-positive PCa cell lines (with GI50 in low micromolar ranges), cellular, biochemical and in silico binding of 3d in AR ligand-binding domain. Moreover, compound 3d was shown to be potent even ex vivo in patient-derived tissues, which highlights the therapeutic potential of A-ring-fused pyrazoles. Table of content graphic O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY HighlightsO_LIA-ring-fused pyrazoles of 5-dihydrotestosterone were introduced as AR modulators C_LIO_LISAR study of 55 differently substituted derivatives was discussed C_LIO_LICompound 3d suppressed the expression of AR targets in prostate cell lines C_LIO_LICompound 3d caused AR degradation in time-dependent manner C_LIO_LIEx vivo activity of 3d was demonstrated in patient-derived explants C_LI

pharmacology and toxicology↗

bioRxiv2020

Selective vulnerability of supragranular layer neurons in schizophrenia

Schizophrenia is one of the most wide-spread mental brain disorders with complex and largely unknown etiology. To characterize the impact of schizophrenia at a cellular level, we performed single nucleus RNA sequencing of >190,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls (7 vs 11, respectively). In addition, to correlate data with cortical anatomy, >100,000 neurons were analyzed topographically by immunohistochemistry in an extended cohort of cases with schizophrenia and controls (10 vs 10). Compositional analysis of RNA sequencing data revealed reduction in relative abundance across all families of GABAergic neurons and a concomitant increase in principal neurons, which was most pronounced for supragranular subtypes (layers 2-3). Moreover, supragranular subtypes of GABAergic interneurons showed most dramatic transcriptomic changes. These results were substantiated by histological analysis, which revealed a reduction in the density of calretinin, calbindin and parvalbumin GABAergic interneurons particularly in layer 2. Common effect of schizophrenia on supragranular neuronal networks was underlined by downregulation of protein processing genes and upregulation of neuronal development/plasticity genes across supragranular subtypes of principal neurons and GABAergic interneurons. In situ hybridization and spatial transcriptomics further confirmed supragranular layer neuron vulnerability, revealing complexity of schizophrenia-affected cortical circuits. These point towards general network impairment within supragranular layers being a core substrate associated with schizophrenia symptomatology.

neuroscience↗

bioRxiv2020

Characterizing the Human Heart Rate Circadian Pacemaker through Widely Available Wearable Devices

The effects of real-world stimuli and how they vary across individuals remains largely unknown for lack of a continuous real-world circadian marker. Here, we show how an underlying circadian rhythm in heart rate (CRHR) can be extracted from several widely used wearables. Analysis of over 130,000 days of data from medical interns on rotating shifts shows how CRHR dynamics are distinct from those of sleep-wake timing and vary greatly among individuals. Analysis of circadian timekeeping in travelers in 5 continents shows how the circadian timekeeping more carefully controls wake time rather than sleep time. We determine a personalized phase response curve (PRC) of CRHR to activity for each individual, representing the first passive and personalized determination of how human circadian timekeeping continuously changes due to real-world stimuli. These results collectively establish CRHR as a practical method to study circadian rhythms in the real world. eTOC BlurbWe show how the circadian rhythm in heart rate can be extracted from real world data collected by wearables. Studying data from a large cohort of medical interns working on shifts, we find very interesting dynamics of this circadian rhythm that are independent of the acute effects of activity or sleep-wake timing. These techniques can also determine personalized parameters of circadian timekeeping.

systems biology↗