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

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

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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.

Original languageEnglish (US)
Pages (from-to)3101-3117
Number of pages17
JournalJournal of Physiology
Volume588
Issue number16
DOIs
StatePublished - Aug 15 2010

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Interstitial Cells of Cajal
Stem Cell Factor
Stomach
Oxidative Stress
Neurons
Smooth Muscle Myocytes
Smooth Muscle Myosins
Polymerase Chain Reaction
Nitric Oxide Synthase Type I
Breath Tests
Gastric Emptying
Thromboplastin
Gastric Mucosa
Nutritional Status
Immunoenzyme Techniques
Insulin-Like Growth Factor I
Fluorescence Microscopy
Confocal Microscopy
Cell Differentiation
Flow Cytometry

ASJC Scopus subject areas

  • Physiology

Cite this

Izbeki, F., Asuzu, D. T., Lorincz, A., Bardsley, M. R., Popko, L. N., Choi, K. M., ... Ordog, T. (2010). Loss of Kitlow progenitors, reduced stem cell factor and high oxidative stress underlie gastric dysfunction in progeric mice. Journal of Physiology, 588(16), 3101-3117. https://doi.org/10.1113/jphysiol.2010.191023

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

In: Journal of Physiology, Vol. 588, No. 16, 15.08.2010, p. 3101-3117.

Research output: Contribution to journalArticle

Izbeki, F, Asuzu, DT, Lorincz, A, Bardsley, MR, Popko, LN, Choi, KM, Young, DL, Hayashi, Y, Linden, DR, Kuro-o, M, Farrugia, G & Ordog, T 2010, 'Loss of Kitlow progenitors, reduced stem cell factor and high oxidative stress underlie gastric dysfunction in progeric mice', Journal of Physiology, vol. 588, no. 16, pp. 3101-3117. https://doi.org/10.1113/jphysiol.2010.191023
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. / Loss of Kitlow progenitors, reduced stem cell factor and high oxidative stress underlie gastric dysfunction in progeric mice. In: Journal of Physiology. 2010 ; Vol. 588, No. 16. pp. 3101-3117.
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AU - Popko, Laura N.

AU - Choi, Kyoung Moo

AU - Young, David L.

AU - Hayashi, Yujiro

AU - Linden, David R.

AU - Kuro-o, Makoto

AU - Farrugia, Gianrico

AU - Ordog, Tamas

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