ObjectiveInsulin-like peptide-5 (INSL5) is an orexigenic gut hormone found in a subset of colonic and rectal enteroendocrine L-cells together with the anorexigenic hormones glucagon-like peptide-1 (GLP-1) and peptideYY (PYY). Unlike GLP-1 and PYY, INSL5 levels are elevated by calorie restriction, raising questions about how these hormones respond to different stimuli when they arise from the same cell type. The aim of the current study was to identify whether and how INSL5, GLP-1 and PYY are co-secreted or differentially secreted from colonic L-cells.MethodsAn inducible reporter mouse (Insl5-rtTA) was created to enable selective characterisation of Insl5-expressing cells. Expression profiling and Ca2+-dynamics were assessed using TET-reporter mice. Secretion of INSL5, PYY, and GLP-1 from murine and human colonic crypt cultures was quantified by tandem mass spectrometry. Vesicular co-localisation of the three hormones was analysed in 3D-SIM images of immunofluorescently-labelled murine colonic primary cultures and tissue sections.ResultsINSL5-producing cells expressed a range of G-protein coupled receptors previously identified in GLP-1 expressing L-cells, including Ffar1, Gpbar1, and Agtr1a. Pharmacological or physiological agonists for these receptors triggered Ca2+ transients in INSL5-producing cells and stimulated INSL5 secretion. INSL5 secretory responses strongly correlated with those of PYY and GLP-1 across a range of stimuli. The majority (>80%) of secretory vesicles co-labelled for INSL5, PYY and GLP-1.ConclusionsINSL5 is largely co-stored with PYY and GLP-1 and all three hormones are co-secreted when INSL5-positive cells are stimulated. Opposing hormonal profiles observed in vivo likely reflect differential stimulation of L-cells in the proximal and distal gut.

Cardiomyocytes, the cells generating contractile force in the heart, are connected to each other through a highly specialised structure, the intercalated disc (ID), which ensures force transmission and transduction between neighbouring cells and allows the myocardium to function in synchrony. In addition, cardiomyocytes possess an intrinsic ability to sense mechanical changes and to regulate their own contractile output accordingly. To achieve this, some of the components responsible for force transmission have evolved to sense changes in tension and to trigger a biochemical response that results in molecular and cellular changes in cardiomyocytes. This becomes of particular importance in cardiomyopathies, where the heart is exposed to increased mechanical load and needs to adapt to sustain its contractile function. In this review, we will discuss key mechanosensing elements present at the intercalated disc and provide an overview of the signalling molecules involved in mediating the responses to changes in mechanical force. Keywords Cardiomyopathy. Mechanobiology. Cell-cell contact. Intercalated disc. Cytoskeleton Mechanical cues in the heart Mechanical stimuli play a key role in both heart morphogenesis and in the mature heart. During heart development, mechanical forces orchestrate the molecular and cellular changes that transform the linear tubular heart into a multichambered machine with four valves (Lindsey et al. 2014). In the chick embryo, primordial heart contraction and the resulting pulsatile blood flow occurs before active oxygen transport is required (Burggren 2004), suggesting that contractile force is required not only for blood pumping but also for morphogenesis. Internal forces from cardiac contraction exert strain on the cell-cell junctions, whereas blood flow exerts both perpendicular (cyclic strain) and parallel forces (shear stress) to the vessel wall (Granados-Riveron and Brook 2012). In the developing heart, these mechanical forces are essential for shaping the chambered structure as well as for myofibrillogenesis (Geach et al. 2015), whereas in the fully formed heart, these cues are important in maintaining the structural and functional integrity of the myocardium. In cardiomyopathies, increased mechanical load triggers compensatory molecular and cellular changes temporarily allowing the myocardium to sustain pump function, but with time, these adaptive responses fail to meet the increased demand, resulting in cardiac dysfunction and heart failure (reviewed in Harvey and Leinwand 2011; McNally et al. 2013). Cardiomyocyte cytoarchitecture Cells that make up the contractile tissue of the heart, the cardiomyocytes, are characterised by a highly regular architecture of cytoskeletal elements to ensure force generation and transduction with each heartbeat (reviewed in Ehler 2016). Cytoskeletal elements are organised into two major multiprotein complexes: the myofibrils and the intercalated disc (Fig. 1). Myofibrils, consisting of thin, thick and elastic filaments, contain the contractile machine...

Study of variability in domestic animal populations is the foundation of quantitative genetics. Based on statistical methods, the weights of the total phenotype variation that belong to its different fractions (causal components) are quantified: variation due to gene additive effect, variation due to allelic and non-allelic interactions, variation due to environment (general and special), variation due to genotype-environment interaction and possibly variation due to the association between genotype and environment. In this study, during 2017-2020, we used the method of analysis of variance with two sources of variation. The material was represented by 538 individuals from Hucul horse breed analyzed at 18, 30 and 42 months old). The heritability of character was 0.3402±0.1546 (18 months), 0.5549±0.2225 (30 months), 0.4506±0.1895 (42 months), suggest that this is a hereditary condition that follows a quantitative model of inheritance, where the influence of additive genetic factors is moderate to intense. We can conclude that, in this native breed and for this character, a significant share of the phenotypic value is due to the additive effect of genes.

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