Cargando…
Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats
The tumor suppressor p53 is thought to play a key role in the maintenance of cell size and homeostasis, but relatively little is known about its role in skeletal muscle. Based on its ability to suppress cell growth, we hypothesized that inhibiting the function of wild-type p53 through the overexpres...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9385859/ https://www.ncbi.nlm.nih.gov/pubmed/35977948 http://dx.doi.org/10.1038/s41419-022-05160-6 |
_version_ | 1784769680485908480 |
---|---|
author | Langer, Henning T. Mossakowski, Agata A. Sule, Rasheed Gomes, Aldrin Baar, Keith |
author_facet | Langer, Henning T. Mossakowski, Agata A. Sule, Rasheed Gomes, Aldrin Baar, Keith |
author_sort | Langer, Henning T. |
collection | PubMed |
description | The tumor suppressor p53 is thought to play a key role in the maintenance of cell size and homeostasis, but relatively little is known about its role in skeletal muscle. Based on its ability to suppress cell growth, we hypothesized that inhibiting the function of wild-type p53 through the overexpression of a dominant-negative p53 mutant (DDp53) could result in muscle fiber hypertrophy. To test this hypothesis, we electroporated adult rat tibialis anterior muscles with DDp53 and collected the tissue three weeks later. We confirmed successful overexpression of DDp53 on a histological and biochemical level and found pronounced changes to muscle architecture, metabolism, and molecular signaling. Muscle mass, fiber cross-sectional area, and fiber diameter significantly decreased with DDp53 overexpression. We found histopathological changes in DDp53 transfected muscle which were accompanied by increased levels of proteins that are associated with membrane damage and repair. In addition, DDp53 decreased oxidative phosphorylation complex I and V protein levels, and despite its negative effects on muscle mass and fiber size, caused an increase in muscle protein synthesis as assessed via the SUnSET technique. Interestingly, the increase in muscle protein synthesis was concomitant with a decrease in phospho-S6K1 (Thr389). Furthermore, the muscle wasting in the DDp53 electroporated leg was accompanied by a decrease in global protein ubiquitination and an increase in proteasome activity. In conclusion, overexpression of a dominant-negative p53 mutant in skeletal muscle results in decreased muscle mass, myofiber size, histological muscle damage, a metabolic phenotype, and perturbed homeostasis between muscle protein synthesis and degradation. |
format | Online Article Text |
id | pubmed-9385859 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-93858592022-08-19 Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats Langer, Henning T. Mossakowski, Agata A. Sule, Rasheed Gomes, Aldrin Baar, Keith Cell Death Dis Article The tumor suppressor p53 is thought to play a key role in the maintenance of cell size and homeostasis, but relatively little is known about its role in skeletal muscle. Based on its ability to suppress cell growth, we hypothesized that inhibiting the function of wild-type p53 through the overexpression of a dominant-negative p53 mutant (DDp53) could result in muscle fiber hypertrophy. To test this hypothesis, we electroporated adult rat tibialis anterior muscles with DDp53 and collected the tissue three weeks later. We confirmed successful overexpression of DDp53 on a histological and biochemical level and found pronounced changes to muscle architecture, metabolism, and molecular signaling. Muscle mass, fiber cross-sectional area, and fiber diameter significantly decreased with DDp53 overexpression. We found histopathological changes in DDp53 transfected muscle which were accompanied by increased levels of proteins that are associated with membrane damage and repair. In addition, DDp53 decreased oxidative phosphorylation complex I and V protein levels, and despite its negative effects on muscle mass and fiber size, caused an increase in muscle protein synthesis as assessed via the SUnSET technique. Interestingly, the increase in muscle protein synthesis was concomitant with a decrease in phospho-S6K1 (Thr389). Furthermore, the muscle wasting in the DDp53 electroporated leg was accompanied by a decrease in global protein ubiquitination and an increase in proteasome activity. In conclusion, overexpression of a dominant-negative p53 mutant in skeletal muscle results in decreased muscle mass, myofiber size, histological muscle damage, a metabolic phenotype, and perturbed homeostasis between muscle protein synthesis and degradation. Nature Publishing Group UK 2022-08-17 /pmc/articles/PMC9385859/ /pubmed/35977948 http://dx.doi.org/10.1038/s41419-022-05160-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Langer, Henning T. Mossakowski, Agata A. Sule, Rasheed Gomes, Aldrin Baar, Keith Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats |
title | Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats |
title_full | Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats |
title_fullStr | Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats |
title_full_unstemmed | Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats |
title_short | Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats |
title_sort | dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9385859/ https://www.ncbi.nlm.nih.gov/pubmed/35977948 http://dx.doi.org/10.1038/s41419-022-05160-6 |
work_keys_str_mv | AT langerhenningt dominantnegativep53overexpressioninskeletalmuscleinducescelldeathandfiberatrophyinrats AT mossakowskiagataa dominantnegativep53overexpressioninskeletalmuscleinducescelldeathandfiberatrophyinrats AT sulerasheed dominantnegativep53overexpressioninskeletalmuscleinducescelldeathandfiberatrophyinrats AT gomesaldrin dominantnegativep53overexpressioninskeletalmuscleinducescelldeathandfiberatrophyinrats AT baarkeith dominantnegativep53overexpressioninskeletalmuscleinducescelldeathandfiberatrophyinrats |