bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/659128

Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

Huang, K.·Miao, T.·Chang, K.·Kang, P.·Jiang, Q.·Simmonds, A. J.·Di Cara, F.·Bai, H.
View original source ↗Export metadata ↓

Abstract

Age is a major risk factor for cardiovascular diseases. Currently, the non-autonomous regulation of age-related cardiac dysfunction is poorly understood. In the present study, we discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes (hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is significantly up-regulated (52-fold) in aged oenocytes. Oenocyte-specific knockdown of Upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of Upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates aging- and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Huang, K., Miao, T., Chang, K., Kang, P., Jiang, Q., Simmonds, A. J., Di Cara, F., Bai, H.. 2019-06-03. Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3. https://doi.org/10.1101/659128

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Functional Assessment and Extended Culture of Human Pediatric Cardiac Tissue Slices for Preclinical Testing

Background: Living human myocardial slices preserve native tissue architecture, but their application to pediatric cardiac physiology or prolonged functional testing remains limited. We adapted a passive culture method for small surgical myocardial specimens obtained from patients with congenital heart disease (CHD). Methods: Atrial and ventricular specimens were obtained from 41 cardiac surgery patients (7.7{+/-}11.1 years; 1 day-49 years). Myocardial tissue was sectioned into slices and studied acutely, or maintained under free floating, rocking cell culture conditions without electrical or mechanical stimulation. Calcium transients were recorded in response to external pacing (0.2-2 Hz) at baseline, and after isoproterenol or norepinephrine exposure. Selected preparations underwent viability, histological, and gene expression analyses. Results: Pacing evoked calcium transients were recorded from all four cardiac chambers, exhibiting expected frequency-dependent shortening. Mean interslice and intraslice coefficients of variation were 11.1% and 7.6%. Viability was 85.8 {+/-} 5.6% post-slicing and 78.8 {+/-} 5.0% after 3-5 hours. Calcium transients remained detectable through 178 days in atrial and 119 days in ventricular slices. Calcium transient durations were relatively stable during extended culture. Beta-adrenergic agonists shortened calcium transient durations (isoproterenol: 32% atrial, 25% ventricular at 0.3 Hz); responses to isoproterenol persisted to approximately 120 days in selected atrial slices and 60 days in ventricular slices. Selected histological features were preserved, although some extracellular matrix and apoptosis related transcripts changed. Conclusions: Small surgical specimens support repeated physiological measurements and pharmacological testing during extended passive culture, providing a platform for human developmental and disease-specific cardiac research.

physiology↗
bioRxiv2026

mTORC1-dependent control of Hedgehog signaling mediates nutrient-responsive licensing of intestinal stem cell differentiation

How progenitor cells couple their metabolic state to the regulation of fate and differentiation remains a fundamental question in tissue development and regeneration. Here, we identify a nutrient-responsive circuit that links progenitor anabolism to differentiation in the Drosophila midgut. We show that the mTORC1 downstream effector PWP1 is necessary and sufficient for differentiation of intestinal stem cell progeny toward the absorptive lineage in fed animals. In progenitors with high mTORC1 activity, PWP1 controls gene expression to promote Hedgehog (Hh) signaling, which cell autonomously drives progenitor differentiation into enterocytes. This circuit is constrained by feedback regulation, as elevated Hh activity inhibits mTORC1 and consequently excludes PWP1 from the nucleus. Disruption of the mTORC1-PWP1-Hh axis causes a progressive failure of enterocyte turnover during aging and reduced lifespan. While the aged midguts retain their barrier function, defective renewal leads to aging-associated deregulation of intestinal metabolism. Collectively, these observations support the concept of growth-dependent licensing of differentiation, whereby the nutrient-responsive anabolic state of a progenitor cell controls its lineage progression, consequently enabling organ renewal.

physiology↗
bioRxiv2026

Site-, strain- and mutation-specific osteopetrosis phenotypes in mice with Clcn7 variants

Background: Autosomal dominant osteopetrosis type II (ADOII) is a rare bone disorder caused primarily by heterozygous mutations in CLCN7 and characterized by increased bone mass yet fragility and marked phenotypic heterogeneity among affected individuals. The biological factors underlying this variability remain poorly understood. We investigated the effects of age, sex, genetic background, and mutation type on bone phenotypes in murine models of ADOII carrying heterozygous Clcn7 F318L/+ or G213R/+ mutations. Methods: Bone microarchitecture was assessed by micro-computed tomography in vertebrae and femora from female and male mice across multiple ages (12, 24, and 52 weeks) and strain backgrounds (FVB/NJ, C57BL/6, and 129). Vertebral biomechanical properties were estimated by micro-finite element analysis, while femoral mechanical properties were measured using three-point bending. Results: Clcn7 F318L/+ mice exhibited significantly increased trabecular bone compared with wild-type littermates at vertebral and femoral sites across the lifespan in both sexes. The magnitude of the vertebral trabecular phenotype increased with age, whereas age-related effects in the femur were more modest and site dependent. Vertebral micro-finite element analysis predicted greater stiffness and ultimate force in F318L/+ mice irrespective of age. Cortical thickness was modestly increased, particularly in female mice, but femoral mechanical properties were largely unchanged. The relative increase in vertebral trabecular bone was similar on the FVB/NJ and C57BL/6 backgrounds in males but greater on C57BL/6 in females, whereas the femoral trabecular and cortical responses were markedly attenuated on C57BL/6 in both sexes. In G213R/+ mice, the relative trabecular phenotype was similar on the C57BL/6 and 129 backgrounds, except for a greater vertebral phenotype in 129 males. Likewise, comparison of F318L/+ and G213R/+ mice demonstrated comparable vertebral phenotypes, although mutation-specific differences emerged at the femur, particularly in males. Conclusion: Collectively, these findings demonstrate that heterozygous Clcn7 mutations produce a robust osteopetrotic phenotype characterized primarily by increased trabecular bone mass that is present regardless of sex, age, genetic background, and mutation type. Age and genetic background modify its magnitude in a site- and sex-specific manner, suggesting that local factors may contribute more strongly to phenotypic variation than the specific disease-causing Clcn7 mutation. These results provide insight into determinants of phenotypic heterogeneity in ADOII and establish a framework for future mechanistic studies of osteopetrotic bone quality and fragility.

physiology↗