Abstract Body (Do not enter title and authors here): Background: Malnutrition is a significant stressor in elderly patients, contributing to cardiovascular morbidity. The molecular mechanisms behind the heart’s response to nutrient deprivation remain unclear. The nutrient-sensitive transcription factor EB (TFEB) plays a key role in cardiomyocyte energy homeostasis. Because TFEB deletion in young cardiomyocyte-specific knockout (cKO) mice caused mild cardiac dysfunction and remodeling, we were interested in investigating this phenotype further during starvation in aged hearts.
Methods: Aged male Tfeb cKO were generated, and wild-type littermates (WT) were used as controls. Both groups underwent 48 h starvation; additional fed WT and cKO mice with ad libitum access served as controls. The mice were then assessed using echocardiography, morphological analysis, and histological examination. Furthermore, Western blotting, proteomics, and metabolomics were employed to quantify alterations in biomarkers associated with cardiac stress and remodeling and metabolic shifts.
Results: Aged cKO mice displayed significantly reduced cardiac function (EF~50%) and enhanced fibrosis compared to WT. Starvation led to further EF decline (≤40%) and exacerbated remodeling in cKO mice, which also showed greater body weight loss, particularly in the liver and brown adipose tissue. Gene and protein expression analyses revealed reduced levels of FAO-, GO-, and OXPHOS-related markers in cKO hearts under starvation. Mass spectrometry confirmed decreased expression of proteins involved in OXPHOS, FAO, and the TCA cycle. TEM analysis revealed increased mitochondrial cross-sectional area (Mito-CSA) in starved WT but not in starved cKO mice. Both fed and starved cKO mice showed reduced Mito-CSA compared to WT. Mitochondrial fission genes were downregulated in starved cKO versus WT. Metabolomic profiling showed elevated levels of skeletal muscle breakdown markers (X1/3_Met_His) in starved WT and cKO mice compared to fed controls. However, starved cKO mice exhibited distinct alterations, including accumulation of sphingolipids and amino acids, alongside reduced acylcarnitine levels, consistent with impaired FAO.
Conclusions: TFEB deletion impairs cardiac function in aged mice and leads to exacerbated structural, molecular, and metabolic deterioration under starvation. These findings highlight TFEB as a central regulator of cardiac resilience during nutrient deprivation. Further studies are needed to clarify the underlying molecular mechanisms.