Aging impairs muscle regeneration by desynchronizing matrix mechano-signaling and macrophage immunomodulation via fibro-adipogenic progenitors

Garcia-Carrizo, F.; Gohlke, S.; Lenihan-Geels, G.; Jank, A.-M.; Leer, M.; Soultoukis, G. A.; Oveisi, M.; Herpich, C.; Garrido, C. A.; Kotsaris, G.; Poehle-Kronawitter, S.; Tsamo-Tetou, A.; Graja, A.; Ost, M.; Villacorta, L.; Knecht, R. S.; Klaus, S.; Schuermann, A.; Stricker, S.; Schmidt-Bleek, K.; Cipitria, A.; Duda, G. N.; Benes, V.; Mueller-Werdan, U.; Norman, K.; Schulz, T. J.

doi:10.1101/2023.11.27.568776

Home/Archive/bioRxiv

bioRxiv · 10.1101/2023.11.27.568776

Aging impairs muscle regeneration by desynchronizing matrix mechano-signaling and macrophage immunomodulation via fibro-adipogenic progenitors

View original source ↗Export metadata ↓

Abstract

Skeletal muscle regeneration depends on the function of fibro/adipogenic progenitors (FAPs). Here we show that aging impairs myogenic stem cells by disrupting the integration of extracellular matrix and immunomodulatory functions within the stem cell niche, thereby promoting fibro/fatty degeneration. We identify the FAP-secreted protein Periostin as a niche factor that is decreased in aged muscle and in circulation of aged humans with low-exercise lifestyle. Periostin controls FAP-expansion after injury and its depletion fate-regulates FAPs towards adipogenesis. This leads to delayed pro- to anti-inflammatory macrophage transition during regeneration. Transplantation of young FAPs with high Periostin secretion, but not Periostin-deficient FAPs, into aged muscle restores inflammation resolution and successful regeneration. Mechanistically, Periostin activates Focal adhesion kinase- and AKT-signaling in macrophages via integrins to promote an anti-inflammatory profile, which synchronizes matrix-derived mechanosensory signaling and immunomodulation. These results uncover a novel role of FAP-based regulation that orchestrates successful muscle regeneration and prevents fibro/fatty degeneration.

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Garcia-Carrizo, F., Gohlke, S., Lenihan-Geels, G., Jank, A.-M., Leer, M., Soultoukis, G. A., Oveisi, M., Herpich, C., Garrido, C. A., Kotsaris, G., Poehle-Kronawitter, S., Tsamo-Tetou, A., Graja, A., Ost, M., Villacorta, L., Knecht, R. S., Klaus, S., Schuermann, A., Stricker, S., Schmidt-Bleek, K., Cipitria, A., Duda, G. N., Benes, V., Mueller-Werdan, U., Norman, K., Schulz, T. J.. 2023-11-27. Aging impairs muscle regeneration by desynchronizing matrix mechano-signaling and macrophage immunomodulation via fibro-adipogenic progenitors. https://doi.org/10.1101/2023.11.27.568776

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

KEEP EXPLORING

Related preprints

bioRxiv2026

Hypothalamic Farnesoid X Receptor deficiency alters energy balance by modulating hepatic glucose production and adipose tissue metabolism through central insulin signaling.

Objectives: The bile acid nuclear receptor Farnesoid X Receptor (FXR, NR1H4) is a major regulator of metabolism and energy homeostasis in peripheral organs. It modulates bile acid, glucose, and lipid metabolism, as well as fat mass and body weight. However, FXR is also expressed in the brain, particularly in the hypothalamus, a key center for the regulation of energy homeostasis. Although one study has demonstrated a role for brain FXR activation in energy balance, its specific hypothalamic role is still unknown. Here, we examined the role of FXR in the mediobasal hypothalamus in the regulation of energy balance. Methods: We used a genetic approach combined with metabolic phenotyping to determine the effect of FXR invalidation in the mediobasal hypothalamus on metabolic parameters involved in the central regulation of energy homeostasis. Results: Our results demonstrate that hypothalamic FXR deficiency induces a positive energy balance, resulting in a reduction in energy expenditure due to alterations in glucose metabolism accompanied by structural changes in white adipose tissues. Conclusion: This study uncovers a previously unrecognized role for hypothalamic FXR in the central homeostatic control of energy balance, providing new insights into its contribution to peripheral glucose metabolism and adipose tissue structural remodeling.

physiology↗

bioRxiv2026

Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia

The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy). Adrenergic stress is also a recognized trigger of arrhythmia in disease. Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the calcium/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2). Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular calcium handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.

physiology↗

bioRxiv2026

Light-cycle time-restricted feeding remodels a hidden layer of the cardiac transcriptome through sex-specific transcript switching

Light-cycle time-restricted feeding disrupts daily cardiovascular and thermoregulatory rhythms, but the molecular effects of light-cycle time-restricted feeding on the heart have been measured only at the level of total gene expression. We used Oxford Nanopore long-read RNA sequencing to resolve the full-length ventricular transcriptome from male and female mice under ad libitum feeding or light-cycle time-restricted feeding across the 24-hour cycle. Greater than 20% of cardiac transcripts represent unannotated variants of known genes absent from the current GENCODE reference annotation. Light-cycle time-restricted feeding reorganizes transcript usage across hundreds of genes, including genes encoding splicing regulators, largely without changing total gene expression. The genes affected are sex-specific, with fewer than 2% of changes shared at the gene, transcript, and transcript-usage levels. We show that transcript-level regulation is a previously underrecognized component of the cardiac response to altered feeding behavior, undetected by conventional short-read approaches.

physiology↗