Communications Biology最新文献

The influential metabolic theory of ecology proposes that metabolic rate determines growth and ecological processes in a universal, size-dependent manner, scaling with body mass^0.75. Conversely, newer life-history-optimisation theory suggests that metabolic scaling varies due to evolutionary optimisation of energy allocation, predicting negative correlation between metabolic rate and growth. However, metabolic scaling has almost exclusively been investigated across individuals or species, not within individuals through ontogeny. By measuring body mass and metabolic rate longitudinally an average 6.6 times within the same 389 individuals from seven fish species, we find that within-individual ontogenetic scaling of standard (maintenance) metabolic rate correlates positively with scaling of growth, while scaling of aerobic scope correlates negatively. Accelerating ontogenetic growth thus appears to come at a cost of reduced metabolic scope to support functions beyond maintenance. Our results suggest that underappreciated variation in growth can explain why metabolic scaling varies, challenging dogmatic ¾-power scaling and life-history-optimisation theory.

Age-related sarcopenia is a growing global health challenge with no approved pharmacotherapies. Here, we integrate network-based drug repurposing and Mendelian randomization to identify rosiglitazone, a PPARγ agonist used in diabetes, as a potential therapeutic candidate for sarcopenia. In aged male C57BL/6JRj murine models, rosiglitazone administration significantly improved muscle strength, mass, and endurance. Multi-omics profiling revealed its mechanism involves gut microbiota remodeling, activation of skeletal muscle Igf1 signaling, suppression of atrophy-related ubiquitin ligases (Atrogin-1/MuRF1), and modulation of protein metabolism, suggesting a coordinated "gut-muscle-metabolism" axis. Genetic analyses further support the causal role of Clostridiaceae/Clostridium in grip strength. Our findings nominate rosiglitazone as a promising intervention for sarcopenia, warranting further clinical investigation.

Hippo-YAP signaling orchestrates transient proliferation during tissue repair and is therefore an attractive target in regenerative medicine. However, it is unclear how YAP integrates mitogen and contact signals to start and stop proliferation. Here we show that reduced contact inhibition, increased mitogen signaling, and YAP-TEAD activation converge on increasing the nuclear cyclin D1/p27 protein ratio during early G1 phase, towards a threshold ratio that dictates whether individual cells enter or exit the cell cycle. YAP increases this ratio in concert with inducing mitogen signaling, by increasing EGFR and other receptors that signal primarily through ERK. After a delay, contact inhibition suppresses YAP activity, which gradually downregulates mitogen signaling and the cyclin D1/p27 ratio. Thus, critical for regeneration without cancer initiation, robust proliferation responses result from a YAP-induced and receptor-mediated prolonged increase in the cyclin D1/p27 ratio, which is reversed by delayed suppression of receptor signaling after contact inhibition of YAP.

Renal interstitial fibrosis (RIF), the central pathological driver of chronic kidney disease (CKD) progression, remains mechanistically incompletely defined. While long non-coding RNAs (lncRNAs) are emerging as critical regulators of CKD, their roles in RIF pathogenesis are poorly understood. Here, we identify the fibrosis-associated lncRNA P4HA2-AS1 as a key modulator of RIF through integrated analyses of unilateral ureteral obstruction (UUO) mice and TGF-β-stimulated human renal tubular epithelial cells (HK-2), combined with RNA sequencing, RNA pull-down, ubiquitination profiling, and autophagic flux assays. P4HA2-AS1 was markedly upregulated in fibrotic kidneys, and its suppression attenuated fibrotic phenotypes in vivo and in vitro while restoring autophagic flux. Mechanistically, P4HA2-AS1 directly binds the E3 ubiquitin ligase TRIM32, impeding its proteasomal degradation. This stabilization enhances TRIM32-mediated K63-linked ubiquitination of ULK1, a master autophagy initiator, leading to aberrant autophagic activation and fibrotic progression. Our study uncovers a previously unrecognized P4HA2-AS1/TRIM32/ULK1 axis that couples dysregulated autophagy to RIF, proposing lncRNA-protein interaction targeting as a therapeutic strategy against renal fibrosis.

Somatic Sertoli cells in the seminiferous tubule provide structural and paracrine support for spermatogenesis. Proper regulation of Sertoli cell cytoskeleton dynamics is essential for this function; however, the regulatory mechanisms remain unclear. Here, we found that polypyrimidine tract-binding protein 1 (PTBP1) maintained cytoskeletal integrity in Sertoli cells via mTORC2 signaling. Sertoli cell-specific Ptbp1 deletion in mice resulted in germ cell loss, blood-testis barrier disruption, and male infertility. Transcriptomic analysis of purified Sertoli cells revealed the dysregulation of cytoskeletal and adhesion-related genes. RNA immunoprecipitation sequencing demonstrated that PTBP1 bound to Rictor mRNA. PTBP1 loss reduced RICTOR protein expression and downstream PKCα activation, impairing the F-actin cytoskeleton. Cytoskeletal defects caused by PTBP1 deficiency were restored by constitutively active PKCα, confirming the functional relevance of the mTORC2-PKCα axis. These findings highlighted PTBP1's role as a post-transcriptional regulator of male fertility through the maintenance of Sertoli cell architecture and spermatogenesis.

Non-coding RNAs, including piwi-interacting RNAs (piRNAs), are known to regulate osteogenic differentiation in bone marrow-derived mesenchymal stem cells (BMSCs); their role in mesenchymal stem cells (MSCs) from diverse origins remains unclear. In this study, we identified piR48444 as a key regulator that is downregulated during the osteogenic differentiation of stem cells from exfoliated deciduous teeth (SHED) but is upregulated in inflamed and aged BMSCs. Functionally, piR48444 inhibited, while its knockdown enhanced osteogenic differentiation across MSCs from multiple sources. Notably, piR48444-depleted MSCs exhibited superior bone defect repair capacity. PiR48444 antagomir promoted bone regeneration in LPS-induced osteolysis mice and aging mice. Mechanistically, we demonstrated that piR48444 targets METTL7A, suppressing BMP2 mRNA m⁶A methylation. Furthermore, we discovered that the METTL7A/eIF4E complex binds to BMP2 mRNA, thereby enhancing its translational efficiency. Our findings establish piR48444 as a negative regulator of MSC osteogenesis through METTL7A-mediated BMP2 m⁶A methylation, highlighting its potential as a therapeutic target to enhance MSC-based bone regeneration strategies.

Pregnant women undergoing assisted reproductive technology (ART) have an increased risk of gestational diabetes mellitus (GDM), potentially linked to altered immune regulation, but the underlying circulating immune features remain unclear. Here we show an integrated single-cell transcriptomic, immune receptor repertoire, and plasma proteomic analysis of peripheral blood from 32 women with GDM and 31 normal pregnancies after ART. GDM is associated with increased proportions of CD8⁺ T cells and elevated plasma levels of CD6, CXCL5, MMP10, and 4E-BP1. Cytotoxic CD8⁺ T cell subsets display enhanced effector and cytotoxic activity, while B cells, monocytes, and natural killer cells exhibit activated phenotypes. Transcription factors from the FOS and JUN families and KLF6 are implicated in immune activation, accompanied by distinct T cell and B cell receptor repertoire features. The hypothesis-generating multi-omic results highlight potential therapeutic targets and offered insights for future research and management ART-associated pregnancy complications.

Hibernators rely on endogenous supplies of amino acids (AAs) and other nutrients to sustain organ function and skeletal muscle mass. Gut microbiota-mediated recycling of urea-nitrogen into AAs has long been considered a mechanism to assist in conserving nitrogen; however, the relevance of urea nitrogen salvage (UNS) to overall host physiology and metabolism is debated. We hypothesized that incorporation of microbially-liberated urea-nitrogen (MLUN) into AAs would be higher in host tissues of hibernating arctic ground squirrels compared to those of summer active squirrels, and that MLUN would support synthesis of anabolic AAs that regulate protein balance. To test this, we injected [¹³C, ¹⁵N₂]-urea into summer squirrels and into squirrels hibernating at an ecologically relevant ambient temperature (-16 °C). We found greater incorporation of MLUN into non-essential AAs and specific essential AAs in several tissues of hibernating squirrels compared to summer. We also observed increased ¹⁵N enrichment in leucine-isoleucine, citrulline and glutamine, anabolic AAs known to influence protein balance and trans-organ nitrogen balance. Compared to studies in which ground squirrels hibernated at ambient temperatures above 0 °C, our results suggest that squirrels hibernating at subzero temperatures may up modulate synthesis of AAs that preserve protein and nitrogen balance during prolonged fasting and inactivity.

Epigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogeneous and dependent on factors such as the genetic background and metabolic state of cells, as well as on-/off-target engagement of individual small-molecule compounds. The molecular study of the extent of this heterogeneity often measures changes in a single cell line. To more comprehensively profile the effects of small-molecule perturbations and their influence on heterogeneous cellular responses, we present a molecular resource based on the quantification of chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitors (HDACi) in non-isogenic cell lines. Through quantitative molecular profiling of 10,621 proteins, these data reveal coordinated molecular remodeling of HDACi treated cancer cells. HDACi-regulated proteins differ greatly across cell lines with consistent (JUN, MAP2K3, CDKN1A) and divergent (CCND3, ASF1B, BRD7) cell-state effectors. Together these data provide valuable insight into cell-type driven and heterogeneous responses that must be taken into consideration when monitoring molecular perturbations in culture models. We have also built a web interface for the extensive amount of data to allow users to explore the data as a resource for understanding chemical perturbation of diverse cell types.

Organ culture systems enabling in vitro spermatogenesis from neonatal mouse testes exist, but differentiation from fetal testes shortly after sex determination remains unsuccessful. Here, we report the in vitro generation of fertile haploid cells from E12.5 fetal testes. While optimizing in vitro spermatogenesis protocols for neonatal testes, we find that supplementing the culture medium with reverse transcriptase inhibitors (RTIs) significantly improves the efficiency of spermatogenesis, by suppressing retrotransposon activity and protecting genomic integrity. Applying this approach, we successfully induce spermatogenesis through to the elongating spermatid by culturing E12.5 fetal testes under hypoxic conditions in RTI-supplemented medium. Notably, microinsemination using in vitro-derived spermatids produces healthy and fertile offspring, confirming their functional competence. These findings demonstrate the faithful in vitro recapitulation of testicular development and complete spermatogenesis from an early fetal stage, providing a valuable platform for investigating early germ cell development and reproductive biology.