11/29/2023 0 Comments Collagen catabolism![]() In the present study, we investigated the effect of LRG1 on extracellular matrix (ECM) integrity in fibroblasts, as well as on skin aging. ![]() Leucine-rich alpha-2-glycoprotein 1 (LRG1) mediates skin repair and fibrosis by stimulating the transforming growth factor-beta (TGF-ß) signaling pathway. , Transforming Growth Factor beta/metabolism We inferred that the decline in SPARC expression in aged skin contributes to process of skin aging by negatively affecting ECM integrity in fibroblasts. These results indicated that SPARC enhanced ECM integrity by activating the TGF-ß signaling pathway in fibroblasts. RT-qPCR confirmed that a subset of differentially expressed genes is induced by SPARC. Transcriptome analysis revealed that SPARC modulated expression of genes involved in ECM synthesis and regulation in fibroblasts. An inhibitor of transforming growth factor-beta (TGF-ß) receptor type 1 reversed the SPARC-induced increase in type I collagen and decrease in MMP-1, and decreased SPARC-induced R-SMAD phosphorylation. In addition, SPARC also induced receptor-regulated SMAD (R-SMAD) phosphorylation. In a three-dimensional culture of foreskin fibroblasts mimicking the dermis, SPARC significantly increased the synthesis of type I collagen and decreased its degradation. Incubating foreskin fibroblasts with recombinant human SPARC led to increased type I collagen production and decreased matrix metalloproteinase-1 (MMP-1) secretion at the protein and mRNA levels. We found decreased SPARC expression in aged skin. The matricellular secreted protein acidic and rich in cysteine (SPARC also known as osteonectin), is involved in the regulation of extracellular matrix (ECM) synthesis, cell-ECM interactions, and bone mineralization. These data demonstrate that the impact of OI on myocardial mechanics includes cardiomyocyte adaptations beyond known direct effects on the extracellular matrix. The data reveal the hypercontractility of OI CMs with rapid rundown when exposed to acute stiffness challenges, extending our understanding of OI. This represents the first assessment of cardiomyocyte mechanics in OI. Together these data confirm multiple CM-level adaptations to low stiffness that extend our understanding of OI in the heart and how CMs respond to extracellular stiffness.NEW & NOTEWORTHY In a rare donation of a heart from an individual with osteogenesis imperfecta (OI), we explored cardiomyocyte (CM) adaptations to low stiffness. Levels of detyrosinated α-tubulin, known to be responsive to extracellular stiffness, were reduced in OI CMs. In response to 48 h of culture on surfaces with physiological (10 kPa) and pathological (50 kPa) stiffness, OI CMs demonstrated a greater reduction in contractility than nonfailing CMs, suggesting that OI CMs may have an impaired stress response. Interestingly, OI CMs were hypercontractile relative to nonfailing controls after 24 h of culture. However, CMs retained normal viscoelastic properties as revealed by nanoindentation. Trabecular stretch confirmed low stiffness on the tissue level. Proteomics and histology confirmed strikingly low expression of collagen 1. Here, we explore the tissue-level and CM-level properties of a heart from a deceased organ donor with OI type I. Although reduced collagen in OI hearts has been associated with reduced myocardial stiffness and left ventricular remodeling, its impact on cardiomyocyte (CM) function has not been studied. Osteogenesis imperfecta (OI) is an extracellular matrix disorder characterized by defects in collagen-1 transport or synthesis, resulting in bone abnormalities.
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