Aging-related sarcopenia represents a significant health concern due to its impact on the quality of life in the elderly. This study elucidates the molecular mechanisms underlying sarcopenia by employing single-cell sequencing and public transcriptome databases to compare young and aged mouse skeletal muscles. Cellular classification and pseudotime analyses differentiated cell types and their interrelationships, revealing a marked reduction in satellite cell numbers and a consistent upregulation of TXNIP (Thioredoxin interacting protein) across various muscle cell populations in aged mice. Further transcriptomic data integration and batch correction from the GEO (Gene Expression Omnibus) database highlighted key differentially expressed genes. The role of TXNIP and its transcriptional regulation by FOXO1 (Forkhead box O1) was confirmed through in vitro experiments, which demonstrated FOXO1's influence on TXNIP expression and its subsequent suppression of glutathione metabolism, leading to satellite cell ferroptosis. Additionally, in vivo studies showed that overexpression of TXNIP in young mice's muscle tissues significantly reduced muscle mass, suggesting its potential role in the initiation of sarcopenia. Our findings suggest that FOXO1-mediated regulation of TXNIP and the disruption of glutathione metabolism are central to the process of sarcopenia, offering new insights into its pathogenesis.
© 2025. The Author(s).

Summary Circadian rhythms are essential for organismal health. Satellite cells (SCs), the muscle resident stem cells, maintain a state of quiescence yet exhibit robust circadian oscillations at the transcriptional level. Although peripheral clocks have been extensively studied in various tissues, how the intrinsic clock of stem cells interacts with the central, distal clock is largely unknown. We used SC-specific reconstitution of the essential clock gene Bmal1 to elucidate the role of the local SC clock and its interplay with the central clock in the mouse brain and found that daily transcriptional control of metabolic processes in SCs depend on central clock input, independent of the SC clock. Central clock-driven genes were involved in lipid metabolism, functionally important for SC-mediated muscle repair, and autophagy was required for their oscillation. In summary, we provide the first evidence of circadian coordination of central and local clocks for control of rhythmic gene expression in quiescent stem cells. Highlights Brain:satellite cell clock communication restores rhythms of core clock machinery in quiescent satellite cells Brain inputs are the dominant regulator of transcript rhythms in SCs, driving the oscillation of lipid metabolic genes. Autophagy in satellite cells is required for the oscillation of lipid metabolic genes. Early phases of muscle regeneration depend on brain-driven circadian signals.

Hematopoiesis in mammal is a complex and highly regulated process in which hematopoietic stem cells (HSCs) give rise to all types of differentiated blood cells. Previous studies have shown that hairy and enhancer of split (HES) repressors are essential regulators of adult HSC development downstream of Notch signaling.
In this study, we investigated the role of HES1, a member of HES family, in fetal hematopoiesis using an embryonic hematopoietic specific Hes1 conditional knockout mouse model by using phenotypic flow cytometry, histopathology analysis, and functional in vitro colony forming unit (CFU) assay and in vivo bone marrow transplant (BMT) assay.
We found that loss of Hes1 in early embryonic stage leads to smaller embryos and fetal livers, decreases hematopoietic stem progenitor cell (HSPC) pool, results in defective multi-lineage differentiation. Functionally, fetal hematopoietic cells deficient for Hes1 exhibit reduced in vitro progenitor activity and compromised in vivo repopulation capacity in the transplanted recipients. Further analysis shows that fetal hematopoiesis defects in Hes1fl/flFlt3Cre embryos are resulted from decreased proliferation and elevated apoptosis, associated with de-repressed HES1 targets, p27 and PTEN in Hes1-KO fetal HSPCs. Finally, pharmacological inhibition of p27 or PTEN improves fetal HSPCs function both in vitro and in vivo.
Together, our findings reveal a previously unappreciated role for HES1 in regulating fetal hematopoiesis, and provide new insight into the differences between fetal and adult HSC maintenance.
© 2024. The Author(s).

Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs.
© 2024 The Authors.

Leukemia is a kind of hematological malignancy originating from bone marrow, which provides essential signals for initiation, progression, and recurrence of leukemia. However, how to specifically deliver drugs to the bone marrow remains elusive. Here, we develop biomimetic vesicles by infusing hematopoietic stem and progenitor cell (HSPC) membrane with liposomes (HSPC liposomes), which migrate to the bone marrow of leukemic mice via hyaluronic acid-CD44 axis. Moreover, the biomimetic vesicles exhibit superior binding affinity to leukemia cells through intercellular cell adhesion molecule-1 (ICAM-1)/integrin β2 (ITGB2) interaction. Further experiments validate that the vesicles carrying chemotherapy drug cytarabine (Ara-C@HSPC-Lipo) markedly inhibit proliferation, induce apoptosis and differentiation of leukemia cells, and decrease number of leukemia stem cells. Mechanically, RNA-seq reveals that Ara-C@HSPC-Lipo treatment induces apoptosis and differentiation and inhibits the oncogenic pathways. Finally, we verify that HSPC liposomes are safe in mice. This study provides a method for targeting bone marrow and treating leukemia.
© 2024. The Author(s).