Details

Autor(en) / Beteiligte

• Izbeki, Ferenc
• Asuzu, David T.
• Lorincz, Andrea
• Bardsley, Michael R.
• Popko, Laura N.
• Choi, Kyoung Moo
• Young, David L.
• Hayashi, Yujiro
• Linden, David R.
• Kuro‐o, Makoto
• Farrugia, Gianrico
• Ordog, Tamas

Titel

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

Ist Teil von

• The Journal of physiology, 2010-08, Vol.588 (16), p.3101-3117

Ort / Verlag

Oxford, UK: Blackwell Publishing Ltd

Erscheinungsjahr

2010

Quelle

Wiley Blackwell Single Titles

Beschreibungen/Notizen

• 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. Storage and processing of ingested food, transport of intestinal contents and waste excretion decline with ageing. Using prematurely ageing mice we show that ageing‐associated decline in stomach functions such as reduced food intake and impaired electrical control of smooth muscle contractions and relaxation are associated with loss of interstitial cells of Cajal (ICC), non‐neuronal cells that serve as electrical pacemakers and mediators of nerve–muscle interactions, rather than overt degeneration of nerve or smooth muscle cells. ICC loss was accompanied by the depletion of their local stem/progenitor cells, reduced factors required for ICC differentiation and increased oxidative stress. Our findings shed new light on how ageing affects stomach functions and identify novel targets for therapeutic intervention that could slow down these changes.