Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy
The ubiquitously expressed adaptor protein Shc exists in three isoforms p46Shc, p52Shc, and p66Shc, which execute distinctly different actions in cells. The role of p46Shc is insufficiently studied, and the purpose of this study was to further investigate its functional significance. We developed un...
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doaj-f3bad463457a44d098f23958f960fd2d2021-06-01T00:08:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-01225237523710.3390/ijms22105237Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated CardiomyopathyBradley Miller0Tatiana Y. Kostrominova1Aron M. Geurts2Andrey Sorokin3Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53266, USADepartment of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine-Northwest, Gary, IN 46408, USADepartment of Physiology, Medical College of Wisconsin, Milwaukee, WI 53266, USADepartment of Medicine, Medical College of Wisconsin, Milwaukee, WI 53266, USAThe ubiquitously expressed adaptor protein Shc exists in three isoforms p46Shc, p52Shc, and p66Shc, which execute distinctly different actions in cells. The role of p46Shc is insufficiently studied, and the purpose of this study was to further investigate its functional significance. We developed unique rat mutants lacking p52Shc and p46Shc isoforms (p52Shc/46Shc-KO) and carried out histological analysis of skeletal and cardiac muscle of parental and genetically modified rats with impaired gait. p52Shc/46Shc-KO rats demonstrate severe functional abnormalities associated with impaired gait. Our analysis of p52Shc/46Shc-KO rat axons and myelin sheets in cross-sections of the sciatic nerve revealed the presence of significant anomalies. Based on the lack of skeletal muscle fiber atrophy and the presence of sciatic nerve abnormalities, we suggest that the impaired gait in p52Shc/46Shc-KO rats might be due to the sensory feedback from active muscle to the brain locomotor centers. The lack of dystrophin in some heart muscle fibers reflects damage due to dilated cardiomyopathy. Since rats with only p52Shc knockout do not display the phenotype of p52Shc/p46Shc-KO, abnormal locomotion is likely to be caused by p46Shc deletion. Our data suggest a previously unknown role of 46Shc actions and signaling in regulation of gait.https://www.mdpi.com/1422-0067/22/10/5237Shc signalingsciatic nervedystrophin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bradley Miller Tatiana Y. Kostrominova Aron M. Geurts Andrey Sorokin |
spellingShingle |
Bradley Miller Tatiana Y. Kostrominova Aron M. Geurts Andrey Sorokin Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy International Journal of Molecular Sciences Shc signaling sciatic nerve dystrophin |
author_facet |
Bradley Miller Tatiana Y. Kostrominova Aron M. Geurts Andrey Sorokin |
author_sort |
Bradley Miller |
title |
Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy |
title_short |
Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy |
title_full |
Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy |
title_fullStr |
Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy |
title_full_unstemmed |
Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy |
title_sort |
double p52shc/p46shc rat knockout demonstrates severe gait abnormalities accompanied by dilated cardiomyopathy |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-05-01 |
description |
The ubiquitously expressed adaptor protein Shc exists in three isoforms p46Shc, p52Shc, and p66Shc, which execute distinctly different actions in cells. The role of p46Shc is insufficiently studied, and the purpose of this study was to further investigate its functional significance. We developed unique rat mutants lacking p52Shc and p46Shc isoforms (p52Shc/46Shc-KO) and carried out histological analysis of skeletal and cardiac muscle of parental and genetically modified rats with impaired gait. p52Shc/46Shc-KO rats demonstrate severe functional abnormalities associated with impaired gait. Our analysis of p52Shc/46Shc-KO rat axons and myelin sheets in cross-sections of the sciatic nerve revealed the presence of significant anomalies. Based on the lack of skeletal muscle fiber atrophy and the presence of sciatic nerve abnormalities, we suggest that the impaired gait in p52Shc/46Shc-KO rats might be due to the sensory feedback from active muscle to the brain locomotor centers. The lack of dystrophin in some heart muscle fibers reflects damage due to dilated cardiomyopathy. Since rats with only p52Shc knockout do not display the phenotype of p52Shc/p46Shc-KO, abnormal locomotion is likely to be caused by p46Shc deletion. Our data suggest a previously unknown role of 46Shc actions and signaling in regulation of gait. |
topic |
Shc signaling sciatic nerve dystrophin |
url |
https://www.mdpi.com/1422-0067/22/10/5237 |
work_keys_str_mv |
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