Loss of Kitlow progenitors, reduced stem cell factor and high oxidative stress underlie gastric dysfunction in progeric mice.
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.
Izbeki
Ferenc
F
Department of Physiology and Biomedical Engineering, Mayo Clinic, Guggenheim 10, 200 1st Street SW, Rochester, MN 55906, USA.
Asuzu
David T
DT
Lorincz
Andrea
A
Bardsley
Michael R
MR
Popko
Laura N
LN
Choi
Kyoung Moo
KM
Young
David L
DL
Hayashi
Yujiro
Y
Linden
David R
DR
Kuro-o
Makoto
M
Farrugia
Gianrico
G
Ordog
Tamas
T
D000200:Action Potentials; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D004195:Disease Models, Animal; D015536:Down-Regulation; D004558:Electric Stimulation; D017615:Enteric Nervous System / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005746:Gastric Emptying; D005753:Gastric Mucosa / Q000378:metabolism*; D005786:Gene Expression Regulation; D005838:Genotype; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D056885:Interstitial Cells of Cajal / Q000378:metabolism; D000090265:Klotho Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009752:Nutritional Status; D018384:Oxidative Stress; D010641:Phenotype; D011371:Progeria / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*; D013270:Stomach / Q000294:innervation / Q000503:physiopathology; D046509:Tissue Culture Techniques
D007328:Insulin; D019089:Stem Cell Factor; D007334:Insulin-Like Growth Factor I; D019009:Proto-Oncogene Proteins c-kit; D005966:Glucuronidase; D000090265:Klotho Proteins