Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis

Viktor J. Horváth, Harsha Vittal, Andrea Lörincz, Hui Chen, Graça Almeida-Porada, Doug Redelman, Tamas Ordog

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Diabetic gastroparesis involves neuropathy, myopathy, and depletion of interstitial cells of Cajal (ICC), which may cause dysrhythmias and impaired neural control. Most murine gastric ICC depend on stem cell factor (SCF) signaling but can also be maintained with insulin or insulin-like growth factor-I (IGF-I). We investigated whether SCF could mediate the actions of insulin and IGF-I. Methods: Expression of insulin receptor, IGF-I receptor, and SCF was studied in gastric muscles and purified ICC by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). The effects of insulin/IGF-I deficiency on SCF, ICC, smooth muscle, and neurons were investigated in nonobese diabetic mice and organotypic cultures by immunohistochemistry, microarrays, and/or quantitative RT-PCR. ICC in organotypic cultures were also studied after immunoneutralization of endogenous SCF. Results: Insulin and IGF-I receptors were detected in smooth-muscle cells and myenteric neurons but not in ICC. Cell-surface expression of SCF was only found in smooth-muscle cells. ICC depletion in diabetes was accompanied by smooth-muscle atrophy and reduced SCF, whereas neuron-specific gene expression remained unchanged. In organotypic cultures, prevention of ICC loss by insulin or IGF-I was paralleled by rescue of smooth-muscle cells and SCF expression but not of myenteric neurons. Immunoneutralization of endogenous SCF caused ICC depletion closely resembling that elicited by insulin/IGF-I deficiency. Conclusions: Reduced insulin/IGF-I signaling in diabetes may lead to ICC depletion and its consequences by causing smooth-muscle atrophy and reduced SCF production. Thus, myopathy may play a more central role in diabetic gastroenteropathies than previously recognized.

Original languageEnglish (US)
Pages (from-to)759-770
Number of pages12
JournalGastroenterology
Volume130
Issue number3
DOIs
StatePublished - Mar 2006
Externally publishedYes

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Interstitial Cells of Cajal
Gastroparesis
Stem Cell Factor
Muscular Diseases
Insulin
Insulin-Like Growth Factor I
Smooth Muscle Myocytes
Smooth Muscle
Neurons
IGF Type 1 Receptor
Muscular Atrophy
Reverse Transcription
Stomach
Immunohistochemistry
Polymerase Chain Reaction
Inbred NOD Mouse
Insulin Receptor

ASJC Scopus subject areas

  • Gastroenterology

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Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis. / Horváth, Viktor J.; Vittal, Harsha; Lörincz, Andrea; Chen, Hui; Almeida-Porada, Graça; Redelman, Doug; Ordog, Tamas.

In: Gastroenterology, Vol. 130, No. 3, 03.2006, p. 759-770.

Research output: Contribution to journalArticle

Horváth, Viktor J. ; Vittal, Harsha ; Lörincz, Andrea ; Chen, Hui ; Almeida-Porada, Graça ; Redelman, Doug ; Ordog, Tamas. / Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis. In: Gastroenterology. 2006 ; Vol. 130, No. 3. pp. 759-770.
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T1 - Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis

AU - Horváth, Viktor J.

AU - Vittal, Harsha

AU - Lörincz, Andrea

AU - Chen, Hui

AU - Almeida-Porada, Graça

AU - Redelman, Doug

AU - Ordog, Tamas

PY - 2006/3

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N2 - Background & Aims: Diabetic gastroparesis involves neuropathy, myopathy, and depletion of interstitial cells of Cajal (ICC), which may cause dysrhythmias and impaired neural control. Most murine gastric ICC depend on stem cell factor (SCF) signaling but can also be maintained with insulin or insulin-like growth factor-I (IGF-I). We investigated whether SCF could mediate the actions of insulin and IGF-I. Methods: Expression of insulin receptor, IGF-I receptor, and SCF was studied in gastric muscles and purified ICC by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). The effects of insulin/IGF-I deficiency on SCF, ICC, smooth muscle, and neurons were investigated in nonobese diabetic mice and organotypic cultures by immunohistochemistry, microarrays, and/or quantitative RT-PCR. ICC in organotypic cultures were also studied after immunoneutralization of endogenous SCF. Results: Insulin and IGF-I receptors were detected in smooth-muscle cells and myenteric neurons but not in ICC. Cell-surface expression of SCF was only found in smooth-muscle cells. ICC depletion in diabetes was accompanied by smooth-muscle atrophy and reduced SCF, whereas neuron-specific gene expression remained unchanged. In organotypic cultures, prevention of ICC loss by insulin or IGF-I was paralleled by rescue of smooth-muscle cells and SCF expression but not of myenteric neurons. Immunoneutralization of endogenous SCF caused ICC depletion closely resembling that elicited by insulin/IGF-I deficiency. Conclusions: Reduced insulin/IGF-I signaling in diabetes may lead to ICC depletion and its consequences by causing smooth-muscle atrophy and reduced SCF production. Thus, myopathy may play a more central role in diabetic gastroenteropathies than previously recognized.

AB - Background & Aims: Diabetic gastroparesis involves neuropathy, myopathy, and depletion of interstitial cells of Cajal (ICC), which may cause dysrhythmias and impaired neural control. Most murine gastric ICC depend on stem cell factor (SCF) signaling but can also be maintained with insulin or insulin-like growth factor-I (IGF-I). We investigated whether SCF could mediate the actions of insulin and IGF-I. Methods: Expression of insulin receptor, IGF-I receptor, and SCF was studied in gastric muscles and purified ICC by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). The effects of insulin/IGF-I deficiency on SCF, ICC, smooth muscle, and neurons were investigated in nonobese diabetic mice and organotypic cultures by immunohistochemistry, microarrays, and/or quantitative RT-PCR. ICC in organotypic cultures were also studied after immunoneutralization of endogenous SCF. Results: Insulin and IGF-I receptors were detected in smooth-muscle cells and myenteric neurons but not in ICC. Cell-surface expression of SCF was only found in smooth-muscle cells. ICC depletion in diabetes was accompanied by smooth-muscle atrophy and reduced SCF, whereas neuron-specific gene expression remained unchanged. In organotypic cultures, prevention of ICC loss by insulin or IGF-I was paralleled by rescue of smooth-muscle cells and SCF expression but not of myenteric neurons. Immunoneutralization of endogenous SCF caused ICC depletion closely resembling that elicited by insulin/IGF-I deficiency. Conclusions: Reduced insulin/IGF-I signaling in diabetes may lead to ICC depletion and its consequences by causing smooth-muscle atrophy and reduced SCF production. Thus, myopathy may play a more central role in diabetic gastroenteropathies than previously recognized.

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