bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.10.06.738500

Impaired glycolysis in bone underlies age-related bone loss in mice

Song, F.·Marmo, T.·Lee, W. D.·Koehnken Sawall, J.·Song, C.·Liao, X.·Ji, X.·Chellappa, K.·McReynolds, M. R.·Baur, J. A.·Thom, C.·Long, F.
View original source ↗Export metadata ↓

Abstract

Bone loss and metabolic dysregulation often coexist in older adults, yet the relationship between age-related changes in bone cell metabolism and bone-forming activity remains unclear. By modeling both conditions in aged mice and using in vivo stable-isotope tracing, we demonstrated that age-related decline in bone formation was coupled with an intrinsic impairment of glycolysis within bone tissue. Impaired glycolysis was associated with reduced protein levels of key glycolysis enzymes, and transcriptomics analyses revealed compensatory upregulation of glycolysis genes in aged bone. Metabolic intervention through long-term caloric restriction prevented age-related trabecular bone loss. Furthermore, osteoblast-specific genetic enhancement of glycolysis, via overexpression of HIF1 or the rate-limiting enzyme PFKFB3, significantly improved osteoblast function and increased bone mass in aged mice. Together, the study identifies glycolytic decline as a cell-autonomous driver of osteoblast deficiency and provides proof of principle that reactivating glycolysis can promote bone accrual in aging.

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Song, F., Marmo, T., Lee, W. D., Koehnken Sawall, J., Song, C., Liao, X., Ji, X., Chellappa, K., McReynolds, M. R., Baur, J. A., Thom, C., Long, F.. 2026-10-06. Impaired glycolysis in bone underlies age-related bone loss in mice. https://doi.org/10.64898/2026.10.06.738500

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

KEEP EXPLORING

Related preprints

bioRxiv2026

Speed judgments during smooth pursuit reflect low gain efference copy

During smooth pursuit eye movements, the visual system must compensate for self-generated retinal motion to achieve stable perception of motion in the environment. This compensation primarily depends on an efferent copy of motor commands. Systematically under- or overweighting the strength of efference copy should lead to correlations between eye movement velocity and perceived object velocity. However, previous examinations of these trial-by-trial perceptual correlations have produced mixed results. It remains unclear how effectively the brain compensates for eye movement induced retinal motion during pursuit, and what this reveals about the way efference copy influences perception. To address this, we developed a speed perturbation paradigm in which 29 participants tracked a moving target that underwent brief speed changes. On each trial, we recorded eye velocity along with perceptual judgments of the sign of the speed change (faster or slower) and confidence ratings for those judgments. Across participants, perceptual and oculomotor sensitivity were correlated (r =0.53), but trial-by-trial perceptual and oculomotor responses appeared independent. A logistic regression model incorporating efference copy gain to predict perceptual reports from stimulus speed and eye speed revealed systematic under-compensation for eye movements; faster eye movements were associated with lower changes in perceived speed. Confidence ratings were well-calibrated to perceptual accuracy and showed a consistent negative relationship with eye movement speed. Collectively, these results are consistent with systematic under compensation for eye movements through the use of efference copy during motion perception.

physiology↗
bioRxiv2026

Hemin Triggers Cytoprotective Lipid Droplet Formation in Pulmonary Microvascular Endothelial Cells

Sickle cell disease (SCD) is characterized by chronic and episodic hemolysis, inducing endothelial cell dysfunction and death. Lipid droplets (LDs) accumulate intracellularly in response to stress but the role of LDs in hemin-stressed pulmonary microvascular cells remain unexplored. We hypothesized that LD formation is an adaptive response that improves endothelial cell survival during hemin-induced stress. We utilized cultures of human lung microvascular endothelial cells (hLMVECs) to test this hypothesis. Hemin alone was able to induce LD biogenesis in culture. In response to hemin treatment, we found an increase in cellular death by lactate dehydrogenase (LDH) assay when LD biogenesis was inhibited with a small molecule inhibitor of diacylglycerol acyltransferase 1 (DGAT1), A922500. Induction of LDs by treatment with oleic acid (OA) coupled with hemin resulted in improved endothelial cell survival. Hemin treatment was able to activate p-JNK and p-P38 signaling, while treatment with OA alone could not induce either signaling pathway. Hemin treatment combined with DGAT1 inhibition resulted in an increase in endothelial cell secreted IL-6 and IL-8 levels as measured by enzyme linked immunosorbent assay (ELISA), demonstrating an increase in endothelial cell dysfunction and stress. Induction of LD formation with oleic acid (OA) treatment resulted a reduction in secreted IL-6 and IL-8. Mitochondrial reactive oxygen species (ROS) production was decreased by OA treatment, as evidenced by MitoSOXRed assay. These data suggest that hLMVECs are protected from hemin-induced inflammation and death by the presence of LDs. Further studies are needed to explore the Hemin-LD-Cell Death axis for translational therapeutic use.

physiology↗
bioRxiv2026

AN INTEGRATED HEART-ON-A-CHIP NAM RESOLVES DISTINCT CLINICAL PHENOTYPES OF MYOCARDIAL ISCHEMIA-REPERFUSION INJURY

Background: Reperfusion is required for myocardial salvage yet itself injures the heart, and cardioprotective interventions that reduce infarct size experimentally have repeatedly failed to improve outcomes in patients. These interventions are evaluated against viability or infarct size alone, whereas ischemia-reperfusion (I/R) injury produces structural, biochemical, and contractile dysfunction in the same tissue. No in vitro new approach methodology (NAM), however, resolves all three within one system. Methods: A NAM was created within a heart-on-a-chip platform, which was constructed by culturing neonatal rat ventricular myocytes (NRVMs) on muscular thin films. Cardiomyocytes were subjected to normoxia, 2 hours of ischemia, and ischemia followed by 2 hours of reperfusion. Sarcomeric architecture was quantified by immunofluorescence, cardiomyocyte injury by LIVE/DEAD staining and cardiac troponin I release into conditioned media, while contractile stress and spontaneous beat frequency were recorded on the same films before and after each condition. Results: Under ischemia, z-line density decreased while architectural metrics were preserved, indicating cell loss rather than sarcomere disorganization. Furthermore, viability decreased, troponin elevated, and every contractile stress component declined, while spontaneous beat frequency was unchanged. Reperfusion fractured this uniform depression. Cell death and troponin release increased further, yet structure was unchanged from ischemia, so every functional change occurred on a depleted but architecturally intact cardiomyocyte population. Systolic stress recovered partially, whereas diastolic stress exceeded baseline, leaving active stress suppressed despite oxygen recovery. Beat frequency increased with pronounced variability. Conclusions: This heart-on-a-chip NAM resolved structural, biochemical, and contractile injury that global indices conflate, distinguishing ischemic from reperfusion pathophysiology. Interestingly, individual readouts corresponded to distinct clinical syndromes of ischemic injury, positioning this platform for future testing of cardioprotective candidates against the full injury phenotype.

physiology↗