The Time-Course of Cancer Cachexia Onset Reveals Biphasic Transcriptional Disruptions in Female Skeletal Muscle Distinct from Males

Authors

Francielly Morena, University of Arkansas, FayettevilleFollow
Seongkyun Lim, University of Arkansas, FayettevilleFollow
Ana Regina Cabrera, University of Arkansas, FayettevilleFollow
Eleanor R. Schrems, University of Arkansas, FayettevilleFollow
Ronald G. Jones, University of Arkansas, Fayetteville
Megan E. Rosa-Caldwell, University of Arkansas, Fayetteville
Tyrone A. Washington, University of Arkansas, FayettevilleFollow
Kevin A. Murach, University of Arkansas, FayettevilleFollow
Nicholas P. Greene, University of Arkansas, FayettevilleFollow

Document Type

Article

Publication Date

7-2023

Keywords

Lewis lung carcinoma; Biological sex dimorphism; RNA-sequencing; Type-II interferon; Cancer cachexia; Mitocarta

Abstract

Background

Cancer-cachexia (CC) is a debilitating condition affecting up to 80% of cancer patients and contributing to 40% of cancer-related deaths. While evidence suggests biological sex differences in the development of CC, assessments of the female transcriptome in CC are lacking, and direct comparisons between sexes are scarce. This study aimed to define the time course of Lewis lung carcinoma (LLC)-induced CC in females using transcriptomics, while directly comparing biological sex differences.

Results

We found the global gene expression of the gastrocnemius muscle of female mice revealed biphasic transcriptomic alterations, with one at 1 week following tumor allograft and another during the later stages of cachexia development. The early phase was associated with the upregulation of extracellular-matrix pathways, while the later phase was characterized by the downregulation of oxidative phosphorylation, electron transport chain, and TCA cycle. When DEGs were compared to a known list of mitochondrial genes (MitoCarta), ~ 47% of these genes were differently expressed in females exhibiting global cachexia, suggesting transcriptional changes to mitochondrial gene expression happens concomitantly to functional impairments previously published. In contrast, the JAK-STAT pathway was upregulated in both the early and late stages of CC. Additionally, we observed a consistent downregulation of Type-II Interferon signaling genes in females, which was associated with protection in skeletal muscle atrophy despite systemic cachexia. Upregulation of Interferon signaling was noted in the gastrocnemius muscle of cachectic and atrophic male mice. Comparison of female tumor-bearing mice with males revealed ~ 70% of DEGs were distinct between sexes in cachectic animals, demonstrating dimorphic mechanisms of CC.

Conclusion

Our findings suggest biphasic disruptions in the transcriptome of female LLC tumor-bearing mice: an early phase associated with ECM remodeling and a late phase, accompanied by the onset of systemic cachexia, affecting overall muscle energy metabolism. Notably, ~ 2/3 of DEGs in CC are biologically sex-specific, providing evidence of dimorphic mechanisms of cachexia between sexes. Downregulation of Type-II Interferon signaling genes appears specific to CC development in females, suggesting a new biological sex-specific marker of CC not reliant on the loss of muscle mass, that might represent a protective mechanism against muscle loss in CC in female mice.

Citation

Morena, F., Lim, S., Cabrera, A. R., Schrems, E. R., Jones, R. G., Rosa-Caldwell, M. E., Washington, T. A., Murach, K. A., & Greene, N. P. (2023). The Time-Course of Cancer Cachexia Onset Reveals Biphasic Transcriptional Disruptions in Female Skeletal Muscle Distinct from Males. BMC Genomics, 24, 374. https://doi.org/10.1186/s12864-023-09462-7

Creative Commons License

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