PGC-1α Overexpression is Not Sufficient to Mitigate Cancer Cachexia in Either Male or Female Mice

Authors

Francielly Morena da Silva, University of Arkansas, FayettevilleFollow
Megan Rosa-Caldwell, University of Arkansas, FayettevilleFollow
Eleanor R. Schrems, University of Arkansas, FayettevilleFollow
Lauren Martinez, University of Arkansas, Fayetteville
Madeline G. Amos, University of Arkansas, Fayetteville
Seongkyun Lim, University of Arkansas, FayettevilleFollow
Ana Regina Cabrera, University of Arkansas, FayettevilleFollow
Jacob L. Brown, University of Arkansas, Fayetteville
Tyrone A. Washington, University of Arkansas, FayettevilleFollow
Nicholas P. Greene, University of Arkansas, FayettevilleFollow

Document Type

Article

Publication Date

9-2022

Keywords

MitoTEMPO; mitochondria; atrogin; ubiquitin-proteasome; PGC-1 alpha; cachexia; biological sex; Lewis lung carcinoma; muscle atrophy

Abstract

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.

Citation

Morena da Silva, F., Rosa-Caldwell, M., Schrems, E. R., Martinez, L., Amos, M. G., Lim, S., Cabrera, A. R., Brown, J. L., Washington, T. A., & Greene, N. P. (2022). PGC-1α Overexpression is Not Sufficient to Mitigate Cancer Cachexia in Either Male or Female Mice. Applied Physiology, Nutrition, and Metabolism, 47 (9), 933-948. https://doi.org/10.1139/apnm-2022-0086

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.