Double transgenic mice overexpressing cyclin T1 and Gαq exhibited significantly reduced LVEF at 9 weeks compared to wild-type mice (38.4% vs 63.3%, p<0.001).
Do sex and age affect heart failure development and molecular remodeling in double transgenic cyclin T1/Gq alpha subunit mice?
Female mice exhibit early resistance to mitochondrial dysfunction and pathological remodeling in a heart failure model, potentially mediated by Rictor inhibition.
Absolute Event Rate: 38.4% vs 63.3%
p-value: p=<0.001
Abstract Background and Purpose Heart failure (HF) remains a leading cause of mortality worldwide, particularly in an aging population. This study investigated age- and sex-dependent differences in disease progression using transgenic mice with HF. The focus was on proteomic and transcriptomic changes, functional impairment, and cardiac remodelling to gain deeper insights into the molecular changes in HF. Methods Double transgenic (DTG) male and female mice overexpressing both cyclin T1 and Gαq under the control of the cardiac-specific α-myosin heavy chain promoter were studied. These mice develop pathological myocardial growth, progressing to HF. Comparative analyses were performed between DTG and wild-type (WT) littermates at 5 and 9 weeks of age (n=4 per group, time point, and sex). Heart function was assessed via small animal echocardiography, while proteomic and transcriptomic profiles of the left ventricles (LVs) were analysed using mass spectrometry and RNA sequencing. Histological analyses, including picrosirius red and wheat germ agglutinin (WGA) staining, were conducted to evaluate fibrosis and myocyte cross-sectional area. Results DTG mice exhibited a progressive decrease in heart function. Regardless of sex, DTG mice showed significantly reduced left ventricular ejection fraction (LVEF) at 9 weeks compared to WT (DTG vs. WT: LVEF: 38.4±10.2% vs. 63.3±4.3%; p0.001) and relative to younger 5-week-old animals (DTG vs. WT: LVEF: 61.1±2.7% vs. 68.6±4%; p=0.16). Functional and morphological changes were clearly visible earlier in DTG males at 5 weeks compared to females. Histological analyses revealed an age-dependent increase in myocyte size in both DTG and WT, and increased fibrosis due to DTG without significant difference between time points. Transcript and protein levels showed quite strong correlations (Pearson r≥0.6, p0.0001) across all compared conditions (strain, time point, sex). The most and strongest differences in protein level (q0.05, FC≥|1.5|) were observed at 9 weeks in DTG mice compared to WT, with more pronounced effects in females (overall: 450↑, 437↓; males: 312↑, 347↓; females: 464↑, 463↓). At 5 weeks, the number of altered proteins was higher in male mice (altered proteins: 761 in males, 572 in females). Enrichment analyses highlighted significant changes in energy metabolism and cardiovascular disease-related pathways. Notably, upstream regulator analysis predicted the inhibition of Rictor, a key component of the mTORC2 complex, exclusively in 5-week-old female mice, suggesting its role in a compensatory response. Conclusion Female mice tend to be more resistant to mitochondrial dysfunction and pathological remodelling at early disease stage. The predicted inhibition of Rictor suggests a potential cardioprotective mechanism in younger females, which needs to be further investigated and evaluated as a therapeutic target. These findings underscore the importance of sex-specific considerations in HF treatment.
Benkner et al. (Sat,) conducted a other in Heart failure (n=32). Double transgenic overexpression of cyclin T1 and Gαq vs. Wild-type (WT) littermates was evaluated on Left ventricular ejection fraction (LVEF) at 9 weeks (p=<0.001). Double transgenic mice overexpressing cyclin T1 and Gαq exhibited significantly reduced LVEF at 9 weeks compared to wild-type mice (38.4% vs 63.3%, p<0.001).