In a groundbreaking study published in Nature, researchers have unveiled a pivotal role for the transcription factor FoxO1 and its regulation of the atrogene Trim63 in protecting young mice from the deleterious effects of polymicrobial sepsis. This discovery sheds light on age-dependent mechanisms of cardiac resilience during severe systemic infections, revealing critical insights with potential therapeutic implications for sepsis management.
Sepsis, a life-threatening condition characterized by an overwhelming immune response to infection, often results in multi-organ failure and high mortality. While the elderly display increased vulnerability, younger populations may survive through yet poorly understood mechanisms of disease tolerance. The latest research conducted by Sanchez and colleagues delves deeply into the cardiac molecular adaptations underlying survival in young hosts confronted with sepsis, highlighting age-specific genetic regulation that differentiates survivors from those who succumb.
Central to this study is the transcription factor FoxO1, known for its roles in metabolism, oxidative stress responses, and muscle homeostasis. By profiling cardiac gene expression in young mice exposed to a lethal dose of polymicrobial sepsis (LD_50), the team identified a distinct set of FoxO1 target genes categorized into four classes based on differential expression patterns correlating with survival or fatality. Notably, two muscle-specific E3 ubiquitin ligases—Trim63 (MuRF1) and Fbxo32 (Atrogin1)—emerged within Class 2 atrogenes, known for their involvement in muscle remodeling.
Data revealed that in young survivors of sepsis, cardiac expression levels of Trim63 and Fbxo32 are significantly upregulated compared to both age-matched uninfected controls and non-surviving infected counterparts. Intriguingly, this dynamic was absent in aged mice, where no correlation between sepsis outcome and cardiac expression of these genes was detected. These results underscore a critical age-related differential regulation of FoxO1 targets in the heart during severe infection.
To unravel whether FoxO1 directly influences the induction of these atrogenes, the researchers administered a specific FoxO1 inhibitor to young infected mice. This intervention effectively prevented the upregulation of Trim63 and Fbxo32 in cardiac tissue, confirming FoxO1’s required role in modulating their expression during sepsis. These mechanistic insights cement FoxO1 as a key regulatory node orchestrating cardiac responses to systemic bacterial challenge.
The functional importance of Trim63, in particular, was evaluated by generating Trim63-deficient mice and subjecting them to low-dose polymicrobial sepsis. Remarkably, young mutants lacking Trim63 exhibited dramatically increased susceptibility to both morbidity and mortality compared to their wild-type littermates. This pronounced vulnerability was accompanied by profound cardiac remodeling marked by gross anatomical alterations, heart weight changes normalized to body weight, and evidence of tissue edema upon histological examination.
Further biochemical analyses revealed elevated serum markers indicative of cardiac injury, such as troponin I and brain natriuretic peptide (BNP), as well as markers for liver and kidney damage. The absence of Trim63 exacerbated systemic organ congestion, emphasizing its critical role beyond the heart. These findings establish Trim63 not only as a molecular marker but as an active mediator of disease tolerance, enabling cardiac and multiorgan integrity during septic insult.
Interestingly, although Trim63 is also expressed in skeletal muscle, its regulation in this tissue during sepsis did not correlate with survival outcomes in young mice, nor did FoxO1 inhibition affect skeletal muscle expression. Skeletal muscle mass was similarly unaffected by Trim63 deficiency during infection, indicating a cardiac-specific function for this gene in the context of sepsis. This tissue specificity highlights nuanced organ-level regulatory programs that govern infection responses.
The study’s implications extend far beyond murine models, as sepsis remains a formidable challenge in human medicine, particularly given the disparate outcomes observed across age groups. Understanding the molecular mechanisms by which young hearts mount protective remodeling could inspire novel therapeutic strategies aimed at enhancing cardiac resilience and systemic tolerance during overwhelming infections.
By delineating the FoxO1-Trim63 axis as a central component of sepsis-induced cardiac remodeling and disease tolerance, this research propels the field toward targeted interventions that leverage endogenous protective pathways. Future exploration into how these pathways intersect with immune system dynamics and metabolic shifts will be crucial to translate these findings into clinical advances.
Moreover, these insights prompt a reevaluation of age-related pathophysiology in sepsis, suggesting that loss of adaptive gene regulation contributes to poorer outcomes in the elderly. Therapeutics designed to activate or mimic FoxO1-induced Trim63 expression in cardiac tissue might provide protective benefits, reducing organ damage and improving survival rates.
In summary, Sanchez et al.’s study highlights a fascinating age-dependent gene regulatory mechanism that safeguards cardiac function during severe bacterial infection. By demonstrating the necessity of FoxO1-mediated induction of Trim63 for survival in young mice, this work identifies promising molecular targets for enhancing disease tolerance in sepsis and potentially other inflammatory conditions.
As sepsis continues to pose a major global health burden, breakthroughs illuminating fundamental disease resilience pathways are critical. This research not only advances our understanding of cardiac biology under infectious stress but also lays the groundwork for innovative approaches to combat sepsis-related morbidity and mortality in vulnerable populations across the lifespan.
Subject of Research: FoxO1-mediated regulation of cardiac atrogenes and disease tolerance in age-dependent responses to polymicrobial sepsis in mice.
Article Title: Disease tolerance and infection pathogenesis age-related tradeoffs in mice.
Article References:
Sanchez, K.K., McCarville, J.L., Stengel, S.J. et al. Disease tolerance and infection pathogenesis age-related tradeoffs in mice. Nature (2026). https://doi.org/10.1038/s41586-025-09923-x
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41586-025-09923-x
Tags: age-dependent cardiac adaptationsAge-related disease tolerancecardiac resilience mechanismsFOXO1 transcription factor rolegenetic regulation of sepsis survivalimmune response to infectionmetabolic responses in disease tolerance.muscle-specific E3 ubiquitin ligasespolymicrobial sepsis in young micetherapeutic implications for sepsisTrim63 and sepsisyoung vs elderly sepsis outcomes
