Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy. Int J Mol Sci 2021 May 15;22(10)
Date
06/03/2021Pubmed ID
34063460Pubmed Central ID
PMC8155973DOI
10.3390/ijms22105237Scopus ID
2-s2.0-85105734035 (requires institutional sign-in at Scopus site) 1 CitationAbstract
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.
Author List
Miller B, Kostrominova TY, Geurts AM, Sorokin AAuthors
Aron Geurts PhD Professor in the Physiology department at Medical College of WisconsinAndrey Sorokin PhD Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCardiomyopathy, Dilated
Gait
Gene Knockout Techniques
Muscle, Skeletal
Protein Isoforms
Rats
Rats, Transgenic
Sciatic Nerve
Src Homology 2 Domain-Containing, Transforming Protein 1
