bioRxiv ScienceSearch

bioRxiv · 10.1101/210104

Growth hormone transgenesis disrupts immune function in muscle of coho salmon (Oncorhynchus kisutch) impacting cross-talk with growth systems

Abstract

The suppression of growth during infection should facilitate resource allocation towards effective immune function. Work supporting this hypothesis has been recently reported in teleosts, demonstrating immune-responsive regulation of the insulin-like growth factor (IGF) system - a key endocrine growth pathway that acts downstream of growth hormone (GH). Skeletal muscle is the main target for growth and energetic storage in fish, yet little is known about how growth is regulated in this tissue during an immune response. We addressed this knowledge gap by characterizing muscle immune responses in size-matched coho salmon (Oncorhynchus kisutch) achieving different growth rates. We compared a wild-type strain with two GH transgenic groups achieving either maximal or highly-suppressed growth - an experimental design that separates GHs direct effects from its influence on growth rate. Fish were sampled 30h post-injection with PBS (control) or mimics of bacterial (peptidoglycan) or viral (Poly:IC) infection. We quantified the mRNA level expression of genes from the GH, GH receptor (GHR), IGF hormone, IGF1 receptor (IGF-1R) and IGF binding protein (IGFBP) families, along with marker genes for muscle growth and host defence genes involved in inflammatory or antiviral responses. We provide strong evidence for dampened immunity in the GH transgenics compared to wild-type animals. Strikingly, the muscle of GH transgenics achieving rapid growth showed no detectable antiviral response, coupled with evidence of a constitutive inflammatory state. GH and IGF system gene expression was also strongly altered by GH transgenesis and fast growth, both for baseline expression levels and responses to immune stimulation. Overall, our findings demonstrate that GH transgenesis disrupts normal immune function and growth-immune cross-talk in muscle, with implications for the health and welfare of farmed salmon.

Source connections

Explore related subjects

Keep this discovery

BibTeXRIS

Alzaid, A., Kim, J.-H., Devlin, R., Martin, S., Macqueen, D.. 2017-10-27. Growth hormone transgenesis disrupts immune function in muscle of coho salmon (Oncorhynchus kisutch) impacting cross-talk with growth systems. https://doi.org/10.1101/210104

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

KEEP EXPLORING

Related preprints

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

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

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