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PGC-1α overexpression is not sufficient to mitigate cancer cachexia in either male or female mice

Cancer cachexia (CC) accounts for 20%–40% of cancer-related deaths. Mitochondrial aberrations have been shown to precede muscle atrophy in different atrophy models, including cancer. Therefore, this study investigated potential protection from the cachectic phenotype through overexpression of peroxi...

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Autores principales: Morena da Silva, Francielly, Rosa-Caldwell, Megan E., Schrems, Eleanor R., Martinez, Lauren, Amos, Madeline G., Lim, Seongkyun, Cabrera, Ana Regina, Brown, Jacob L., Washington, Tyrone A., Greene, Nicholas P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10201462/
https://www.ncbi.nlm.nih.gov/pubmed/35700525
http://dx.doi.org/10.1139/apnm-2022-0086
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author Morena da Silva, Francielly
Rosa-Caldwell, Megan E.
Schrems, Eleanor R.
Martinez, Lauren
Amos, Madeline G.
Lim, Seongkyun
Cabrera, Ana Regina
Brown, Jacob L.
Washington, Tyrone A.
Greene, Nicholas P.
author_facet Morena da Silva, Francielly
Rosa-Caldwell, Megan E.
Schrems, Eleanor R.
Martinez, Lauren
Amos, Madeline G.
Lim, Seongkyun
Cabrera, Ana Regina
Brown, Jacob L.
Washington, Tyrone A.
Greene, Nicholas P.
author_sort Morena da Silva, Francielly
collection PubMed
description Cancer cachexia (CC) accounts for 20%–40% of cancer-related deaths. Mitochondrial aberrations have been shown to precede muscle atrophy in different atrophy models, including cancer. Therefore, this study investigated potential protection from the cachectic phenotype through overexpression of peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α). First, to establish potential of mitochondria-based approaches we showed that the mitochondrial antioxidant MitoTEMPO (MitoT) attenuates myotube atrophy induced by Lewis lung carcinoma (LLC) cell conditioned media. Next, cachexia was induced in muscle-specific PGC-1α overexpressing (MCK-PCG1α) or wildtype (WT) littermate mice by LLC implantation. MCK-PCG1α did not protect LLC-induced muscle mass loss. In plantaris, Atrogin mRNA content was 6.2-fold and ~11-fold greater in WT-LLC vs WT-phosphate-buffered saline (PBS) for males and females, respectively (p < 0.05). MitoTimer red:green ratio for male PGC was ~65% higher than WT groups (p < 0.05), with ~3-fold more red puncta in LLC than PBS (p < 0.05). Red:green ratio was 56% lower in females WT-LLC vs PGC-LLC (p < 0.05). In females, no change in red puncta was noted across conditions. Lc3 mRNA content was ~73% and 2-fold higher in male and female LLC mice, respectively, vs PBS (p < 0.05). While MitoT could mitigate cancer-induced atrophy in vitro, PGC-1α overexpression was insufficient to protect muscle mass and mitochondrial health in vivo despite mitigation of cachexia-associated signaling pathways.
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spelling pubmed-102014622023-05-22 PGC-1α overexpression is not sufficient to mitigate cancer cachexia in either male or female mice Morena da Silva, Francielly Rosa-Caldwell, Megan E. Schrems, Eleanor R. Martinez, Lauren Amos, Madeline G. Lim, Seongkyun Cabrera, Ana Regina Brown, Jacob L. Washington, Tyrone A. Greene, Nicholas P. Appl Physiol Nutr Metab Article Cancer cachexia (CC) accounts for 20%–40% of cancer-related deaths. Mitochondrial aberrations have been shown to precede muscle atrophy in different atrophy models, including cancer. Therefore, this study investigated potential protection from the cachectic phenotype through overexpression of peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α). First, to establish potential of mitochondria-based approaches we showed that the mitochondrial antioxidant MitoTEMPO (MitoT) attenuates myotube atrophy induced by Lewis lung carcinoma (LLC) cell conditioned media. Next, cachexia was induced in muscle-specific PGC-1α overexpressing (MCK-PCG1α) or wildtype (WT) littermate mice by LLC implantation. MCK-PCG1α did not protect LLC-induced muscle mass loss. In plantaris, Atrogin mRNA content was 6.2-fold and ~11-fold greater in WT-LLC vs WT-phosphate-buffered saline (PBS) for males and females, respectively (p < 0.05). MitoTimer red:green ratio for male PGC was ~65% higher than WT groups (p < 0.05), with ~3-fold more red puncta in LLC than PBS (p < 0.05). Red:green ratio was 56% lower in females WT-LLC vs PGC-LLC (p < 0.05). In females, no change in red puncta was noted across conditions. Lc3 mRNA content was ~73% and 2-fold higher in male and female LLC mice, respectively, vs PBS (p < 0.05). While MitoT could mitigate cancer-induced atrophy in vitro, PGC-1α overexpression was insufficient to protect muscle mass and mitochondrial health in vivo despite mitigation of cachexia-associated signaling pathways. 2022-09-01 2022-06-14 /pmc/articles/PMC10201462/ /pubmed/35700525 http://dx.doi.org/10.1139/apnm-2022-0086 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article
Morena da Silva, Francielly
Rosa-Caldwell, Megan E.
Schrems, Eleanor R.
Martinez, Lauren
Amos, Madeline G.
Lim, Seongkyun
Cabrera, Ana Regina
Brown, Jacob L.
Washington, Tyrone A.
Greene, Nicholas P.
PGC-1α overexpression is not sufficient to mitigate cancer cachexia in either male or female mice
title PGC-1α overexpression is not sufficient to mitigate cancer cachexia in either male or female mice
title_full PGC-1α overexpression is not sufficient to mitigate cancer cachexia in either male or female mice
title_fullStr PGC-1α overexpression is not sufficient to mitigate cancer cachexia in either male or female mice
title_full_unstemmed PGC-1α overexpression is not sufficient to mitigate cancer cachexia in either male or female mice
title_short PGC-1α overexpression is not sufficient to mitigate cancer cachexia in either male or female mice
title_sort pgc-1α overexpression is not sufficient to mitigate cancer cachexia in either male or female mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10201462/
https://www.ncbi.nlm.nih.gov/pubmed/35700525
http://dx.doi.org/10.1139/apnm-2022-0086
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