Introduction: Cachexia is a condition in which patients experience uncontrollable weight loss, prominently due to a loss in muscle mass and adipose tissue. This can arise from underlying illness, such as heart disease, AIDS, or different cancers. Cachectic patients are at a higher risk of mortality, experience increased chemotherapy toxicity, and have an overall worsened quality of life. Additionally, cancer cachexia can result in cardiac muscle wasting, which can lead to heart failure. The effect of cancer cachexia has been predominantly focused on skeletal muscle, whereas the impact on cardiac muscle is much less explored. This project aims to investigate the effect of cancer cachexia on cardiac muscle, using a newly developed mouse model. The KPP mouse model presents phenotypic similarities to patients with pancreatic cancer, in which the incidence of cachexia is remarkably high. Given that ribosome biogenesis has recently emerged as a core mechanism regulating skeletal muscle mass, we hypothesize that impaired ribosome biogenesis may also play a role in cardiac muscle wasting in a pancreatic mouse model of cancer cachexia. Methods: Fifteen (7 females and 8 males) KPP mouse hearts alongside twenty-five (13 females and 12 males) littermate controls were collected at 15-20% loss of body mass (advanced or refractory cachexia). Five hours prior to collection, mice were injected with 5-Ethynyl-Uridine (5-EU), a nucleoside analog of uridine, to label nascent RNA. RNA was extracted from the heart apex using DirectZol columns with DNAse treatment (Zymo Research) followed by nascent RNA isolation through 5-EU pulldown. Following cDNA synthesis of both nascent and total RNA fractions, Real-Time PCR analysis of 45S pre-rRNA, a bottleneck step of ribosome biogenesis, alongside other relevant genes, was performed. Statistical analyses were performed using one tailed t-tests. Results: KPP mouse hearts displayed a significantly lower mass (p< 0.0001 in males and females) compared to their littermate controls. Total RNA concentration per milligram of tissue was decreased significantly in cachectic mice (p=0.0003 in males, p=0.0351 in females). Despite the decreased total rRNA in cachectic mice, unexpectedly, ribosome biogenesis was upregulated. 4S pre-rRNA was upregulated by ~2.5 fold in the nascent fraction (p< 0.0001), although it was stable in the total RNA fraction (p=0.947). Conclusion: The data indicate that cancer cachexia causes cardiac muscle wasting, which is associated with reduction of total ribosomal RNA in cardiac muscle. However, contrary to our hypothesis, 45S pre-rRNA was upregulated in the nascent fraction of the KPP mice exhibiting refractory or late-stage cachexia. We conclude that ribosome biogenesis appears to increase in refractory condition, potentially overcompensating or to rescue the lower total rRNA levels. In the future, we aim to determine the rate of ribosome biogenesis from mouse hearts collected at pre-cachexia ( ≤5%) and cachexia ( ≤15% of body weight loss). 1R15AR083675-01 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Rossello et al. (Fri,) studied this question.