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

IBD-Derived Colonic Fibroblasts Exhibit an Osteopontin-Enriched Secretome, and Osteopontin Restrains Human Colonic Organoid Maturation

Background: Intestinal fibroblasts are extensively remodeled in inflammatory bowel disease (IBD), yet the soluble stromal signals that directly influence epithelial maturation remain incompletely understood. We examined whether fibroblasts derived from inflamed IBD colon display an osteopontin (OPN; SPP1)-enriched secretory phenotype and whether extracellular OPN directly modifies non-neoplastic human colonic epithelium. Methods: Conditioned media from 5 noninflamed-associated fibroblast (NAF) and 4 inflammatory-associated fibroblast (IAF) cultures were analyzed in the validated multi-donor cytokine-array matrix, with orthogonal SPP1 RT-qPCR validation in a complementary fibroblast cohort. Recombinant OPN was then tested in human colonic organoids from 3 donors using donor-resolved molecular and functional analyses under standard, fibroblast-conditioned, and WNT-modified culture conditions. Donor identity defined biological replication. Results: OPN showed the strongest positive rank-based separation between IAF and NAF cultures: all 4 IAF values were higher than all 5 NAF values (Cliff's delta=1.00; exact Mann-Whitney P=0.0159; median ratio=3.64; Benjamini-Hochberg q=.19). Fibroblast RT-qPCR showed approximately 10-fold higher mean SPP1 expression in IAF than NAF cultures (P<.05). In organoids, OPN consistently reduced KRT20, FABP1, CA2, and MUC2 from Day 5 to Day 9. SOX9, HES1, and NOTCH1 increased at Day 9, whereas LGR5 and ALDH provided no evidence of canonical stem-cell expansion. Organoid-area and EdU responses were modest and donor dependent. Conclusions: IBD-derived colonic fibroblasts can display an OPN-enriched secretory phenotype. In human colonic organoids, OPN is sufficient to impair epithelial maturation, whereas its effects on growth and proliferation are variable and depend on the surrounding niche.

physiology↗

bioRxiv2026

A multiscale analysis of liver lobule fibrosis and its impact on drug propagation and metabolism - a DLA approach

Employing DLA methods, this paper explores the self-assembly of collagen fibers and resulting fibrosis at three scales up to the scale of regular lobule models. This allows a mechanistic exploration of the effects of collagen on drug transport (flow and diffusion) and metabolism. In addition, this method permits an analysis of fiber growth characteristics. First, variations of the DLA method of Parkinson et al (1994) will be used to generate multiple explicit collagen microfibril self-assembly using DLA particles in one dimension using cubic grid blocks of (4 mm)3 in a 240 x 20 x 20 grid model. The second stage will be to assess the consequences of various densities of these fibers in three dimensions on flow reductions at a higher scale. Here we utilize DLA methods in cubic grid blocks of (80 nm)3 to mimic 3D collagen self-assembly of fibrils. We then apply a pressure gradient or specified flow rates across a spatially gridded version of these models to quantify flow effects. This region represents a local zone of liver tissue affected by fibrosis. Analytic models of fibrotic effects on flow are employed for comparison. A third stage explores the implications of fibrosis in a liver lobule model using multiple grid blocks of size 3200 mm to represent the lobule tissue. Here, a continuum model of fiber density is employed, based on the previous two scales. The model also includes the effects of additional grid blocks representing sinusoidal flow paths found in the lobule. We contrast and quantify drug propagation and metabolism of molecular dissolved versus nanoparticle delivery vehicles in fibrotic media, achieved by upscaling explicit collagen distributions to appropriate average values.

physiology↗

bioRxiv2026

Pulmonary pressure load shapes right ventricular molecular remodelling in dilated cardiomyopathy

Right ventricular (RV) adaptation to pulmonary hypertension determines outcome in dilated cardiomyopathy (DCM), but the molecular mechanisms of the transition to decompensation remain unclear. We analysed RV tissue from explanted hearts of patients with end-stage DCM using single-nucleus RNA sequencing (n=21), mass spectrometry and Olink Reveal proteomics (both n=44), and integrated these molecular profiles with echocardiographic and right-heart catheterisation measures to identify molecular correlates of RV dysfunction. Mean pulmonary arterial pressure was the dominant correlate of RV transcriptional remodelling, particularly in cardiomyocytes, where higher pressure was associated with contractile remodelling, autophagy, vesicle trafficking and glucose metabolism. In contrast, RV decompensation was characterised by immune activation and reduced oxidative phosphorylation exclusively at the proteomic level. Integrative multi-omics factor analysis (MOFA) further identified fibrosis as the dominant molecular program shared across transcriptomic and proteomic layers. Together, these findings indicate molecular adaptation to pressure load and tissue fibrosis during progression towards RV failure.

physiology↗