Loss of Kitlow progenitors, reduced stem cell factor and high oxidative stress underlie gastric dysfunction in progeric mice.

Publication Type:

Journal Article

Source:

The Journal of physiology, Volume 588, Issue Pt 16, p.3101-17 (2010)

Keywords:

Action Potentialsdigestive disease, digestive deseases Animalsdigestive disease, digestive deseases Blotting, Westerndigestive disease, digestive deseases Cell Differentiationdigestive disease, digestive deseases Disease Models, Animaldigestive disease, digestive deseases Down-Regulationdigestive disease, digestive deseases Electric Stimulationdigestive disease, digestive deseases Enteric Nervous Systemdigestive disease, digestive deseases Flow Cytometrydigestive disease, digestive deseases Fluorescent Antibody Techniquedigestive disease, digestive deseases Gastric Emptyingdigestive disease, digestive deseases Gene Expression Regulationdigestive disease, digestive deseases Genotypedigestive disease, digestive deseases Glucuronidasedigestive disease, digestive deseases Insulindigestive disease, digestive deseases Insulin-Like Growth Factor Idigestive disease, digestive deseases Interstitial Cells of Cajaldigestive disease, digestive deseases Micedigestive disease, digestive deseases Mice, Mutant Strainsdigestive disease, digestive deseases Microscopy, Confocaldigestive disease, digestive deseases Mutationdigestive disease, digestive deseases Myocytes, Smooth Muscledigestive disease, digestive deseases Nutritional Statusdigestive disease, digestive deseases Oxidative Stressdigestive disease, digestive deseases Phenotypedigestive disease, digestive deseases Progeriadigestive disease, digestive deseases Proto-Oncogene Proteins c-kitdigestive disease, digestive deseases Reverse Transcriptase Polymerase Chain Reactiondigestive disease, digestive deseases Stem Cell Factordigestive disease, digestive deseases Stem Cellsdigestive disease, digestive deseases Stomachdigestive disease, digestive deseases Tissue Culture Techniques

Abstract:

Gastrointestinal functions decline with ageing leading to impaired quality of life, and increased morbidity and mortality. Neurodegeneration is believed to underlie ageing-associated dysmotilities but the mechanisms have not been fully elucidated. We used progeric mice deficient in the anti-ageing peptide Klotho to investigate the contribution of key cell types of the gastric musculature to ageing-associated changes in stomach function and the underlying mechanisms. Klotho expression, enteric neurons, interstitial cells of Cajal (ICC), smooth muscle cells and electrical activity were assessed by immunofluorescence, confocal microscopy, 3-dimensional reconstruction, flow cytometry, quantitative RT-PCR, Western immunoblotting and intracellular recordings. Gastric emptying of solids was analysed by the [13C]octanoic acid breath test. Circulating and tissue trophic factors were measured by enzyme immunoassays and quantitative RT-PCR. The role of oxidative stress was investigated in organotypic cultures. Klotho expression was detected in gastric glands, myenteric neurons and smooth muscle cells. Progeric Klotho-deficient mice had profound loss of ICC and ICC stem cells without a significant decrease in neuron counts, expression of neuronal nitric oxide synthase or smooth muscle myosin. Slow wave amplitude and nitrergic inhibitory junction potentials were reduced while solid emptying was unchanged. Klotho-deficient mice were marantic and had low insulin, insulin-like growth factor-I and membrane-bound stem cell factor. Klotho deficiency accentuated oxidative stress and ICC loss. We conclude that Klotho-deficient, progeric mice display a gastric phenotype resembling human ageing and involving profound ICC loss. Klotho protects ICC by preserving their precursors, limiting oxidative stress, and maintaining nutritional status and normal levels of trophic factors important for ICC differentiation.