Biology subjects

Citu, C.

Publications and source records attributed to Citu, C..

4 recordsLinked to original sources

bioRxiv2026

Estrogen-related receptor signaling counters sarcopenia and preserves exercise fitness in naturally aged mice

BackgroundEstrogen-related receptor gamma (ERR{gamma}) drives an exercise mimicking aerobic gene program in the skeletal muscle that could be beneficial in aging. We have investigated the effect of chronic ERR{gamma} activation on minimizing sarcopenia. MethodsExperiments were performed in muscle specific ERR{gamma} transgenic (TG) mice and wild type (WT) littermates, at young (4-5 months) and old (24-26 months) age. In the skeletal muscle, global gene expression changes, as well as myofiber histological changes in fiber type, size, vascular supply and neuromuscular junction (NMJ), and mitochondrial content were measured. Functional analysis was performed using in vivo muscle contraction assay. Exercise fitness was measured using treadmill sprint and endurance test. Gene and protein expression was measured using QPCR and Westerns, respectively. ResultsERR{gamma} activates a pan-ERR aerobic program in the skeletal muscle to increase expression of 574 genes including ERR, mitochondrial homeostasis (e.g. Mfn1, Opa1, Drp1, Fis1, and Tfam), vascularization (e.g. Vegfa, Angpt1, Fgf1), and neuromuscular junction (NMJ) (e.g. Nrp1, Aspa, Ptprm, Cxcr4), simultaneously suppressing the expression of atrophy related genes (e.g. Atrogin1, Traf6, Nedd4, Myd88, p21). ERR{gamma} increases mitochondrial content [Mitochondrial area: old TG vs. WT, 2.00 fold; young TG vs. WT, 1.32 fold], oxidative capacity [NADH-TR activity: old TG vs. WT, 1.20 fold; young TG vs. WT, 1.22 fold] and myofiber type [2a: old TG (687{+/-}258) vs. WT (252{+/-}71); young TG (797{+/-}168) vs. WT (440{+/-}76); 2x: old TG 1348{+/-}87 vs. WT 976{+/-}219; young TG 1131{+/-}135 vs. WT 936{+/-}84; 2b: old TG (798{+/-}103) vs. WT (1628{+/-}148); young TG (967{+/-}133) vs. WT (1623{+/-}189)], and capillarity [capillary-to-myofiber ratio: old TG (3.25{+/-}0.19) vs. WT (2.41{+/-}0.16); young TG (3.41{+/-}0.21) vs WT (2.59{+/-}0.2)] and [NMJ number [old TG (67{+/-}8) vs. WT (40{+/-}9); young TG (77{+/-}11) vs WT (77{+/-}7)], mitigating age-related loss of NMJ and myofiber cross-sectional area [old TG (1570{+/-}147{micro}m2) vs. WT (1692.5{+/-}208{micro}m2) WT; young TG (1828.15{+/-}132.8{micro}m2) vs. WT (2109.7{+/-}296.8{micro}m2)]. ERR{gamma} overexpression preserves muscle contractility with aging [Fatigue resistance: 22.72% reduction in force in old vs. young WT; 3.11% reduction in force between old vs. young TG]. Furthermore, ERR{gamma} maintains exercise fitness in old mice [Running: old TG (2964.52{+/-}405m) vs. old WT (910.75{+/-}6034m); young TG (2232.43{+/-}193.64m) vs. young WT (1366.76{+/-}60.76m)]. ConclusionsERR{gamma} drives a pan-ERR and counter sarcopenic gene program enhancing oxidative myofiber type, mitochondrial content, vasculature, and NMJ in aging muscle. Consequently, ERR{gamma} minimizes myofiber atrophy, preserves contractility, and improves exercise fitness in old mice. Therefore, ERRs are potential translational targets for combating sarcopenia.

physiology↗

bioRxiv2025

Estrogen-related receptor alpha promotes skeletal muscle regeneration and mitigates muscular dystrophy

Skeletal muscle regeneration in chronic muscle diseases such as Duchenne Muscular Dystrophy (DMD) has remained clinically unsurmountable. Estrogen-related receptor alpha (ERR) plays a critical role in adult skeletal muscle metabolism and exercise fitness. Whether ERR activation can drive muscle regeneration and mitigation of dystrophy in DMD is not known. We have investigated ERR signaling in pre-clinical models of acute muscle injury and DMD. ERR is induced in differentiating C2C12 myoblast and regenerating muscle. ERR silencing suppressed proliferation and differentiation in C2C12 myoblasts. RNA sequencing revealed that angiogenic factor and proliferation genes were downregulated by ERR knockdown in proliferating cells, whereas oxidative mitochondrial and differentiation regulator genes were downregulated in differentiating cells. In accordance with in vitro findings, transgenic ERR overexpression in rodent skeletal muscle stimulates muscle regeneration after acute BaCl2 injury, which is accompanied by enhanced angiogenesis and mitochondrial biogenesis. Notably, ERR and its angiogenic and metabolic target gene expression is suppressed in muscle stem cells (MuSCs) derived from dystrophic muscles in mdx mice, coinciding with proliferation and differentiation defect in these cells. Loss of ERR and its target gene expression was recapitulated in adult dystrophic mdx muscles. Consequently, muscle specific ERR overexpression in mdx mice restored angiogenic and metabolic gene expression, induced vascular and oxidative remodeling, alleviated baseline muscle damage, and boosted regeneration after BaCl2 injury in dystrophic muscle. Our studies demonstrate a pro-regenerative role of ERR and its deficiency in dystrophic muscles and its MuSCs. ERR restoration could be a therapeutic strategy for DMD through angio-metabolic gene program.

physiology↗

bioRxiv2024

Identification and catalogue of viral transcriptional regulators in human diseases

Viral genomes encode viral transcriptional regulators (vTRs) that manipulate host gene expression to facilitate replication and evade immune detection. Nevertheless, their role in non-cancerous diseases remains largely underexplored. Here, we unveiled 268 new candidate vTRs from 14 viral families. We mapped vTRs genome-wide binding profiles and identified their potential human targets, which were enriched in immune-mediated pathways, neurodegenerative disorders, and cancers. Through vTR DNA-binding preference analysis, 283 virus-specific and human-like motifs were identified. Prioritized Epstein-Barr virus (EBV) vTR target genes were associated with multiple sclerosis (MS), rheumatoid arthritis, and systemic lupus erythematosus. The partitioned heritability study among 19 diseases indicated significant enrichment of these diseases in EBV vTR-binding sites, implicating EBV vTRs roles in immune-mediated disorders. Finally, drug repurposing analysis pinpointed candidate drugs for MS, asthma, and Alzheimers disease. This study enhances our understanding of vTRs in diverse human diseases and identifies potential therapeutic targets for future investigation.

bioinformatics↗

bioRxiv2024

Single-nucleus multiomics reveals the disrupted regulatory programs in three brain regions of sporadic early-onset Alzheimer's disease

Sporadic early-onset Alzheimers disease (sEOAD) represents a significant but less-studied subtype of Alzheimers disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type-specific transcriptomic changes and linked candidate cis-regulatory elements (cCREs) across brain regions. We prioritized seven conservative transcription factors in glial cells in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in regulating sEOAD-associated genes. Moreover, we identified the top 25 altered intercellular signaling between glial cells and neurons, highlighting their regulatory potential on gene expression in receiver cells. We reported 38 cCREs linked to sEOAD-associated genes overlapped with late-onset AD risk loci, and sEOAD cCREs enriched in neuropsychiatric disorder risk loci. This atlas helps dissect transcriptional and chromatin dynamics in sEOAD, providing a key resource for AD research.

neuroscience↗