Brunt, K. R. | Search bioRxiv

bioRxiv2024

Yap is a Nutrient Sensor Sensitive to the Amino Acid L-Isoleucine and Regulates Expression of Ctgf in Cardiomyocytes.

Myocardial infarction and reperfusion is a complex injury consisting of many distinct molecular stress patterns that influence cardiomyocyte survival and adaptation. Cell signalling that is essential to cardiac development also presents potential disease-modifying opportunities to recover and limit myocardial injury or maladaptive remodelling. Here we hypothesized that Yap signalling could be sensitive to one or more molecular stress patterns associated with early acute ischemia. Yap, not Taz, patterns of expression differ in post-myocardial infarct compared to peri-infarct tissue suggesting cell-specificity that would be challenging to resolve for causation in vivo. Using H9c2 ventricular myotubes in vitro as a model, Yap levels were most sensitive to nutrient deprivation compared to other stress patterns typified by ischemia within the first hour of stress. Moreover, this is mediated by amino acid availability, dominantly L-isoleucine, and influences the expression of Ctgf--a major determinant of myocardial adaptation after injury. These findings present novel opportunities for future therapeutic development and risk assessment for myocardial injury and adaptation.

pharmacology and toxicology↗

bioRxiv2023

Cardiac atrophy, dysfunction, and metabolic impairments: a cancer-induced heart failure phenotype

Muscle atrophy and weakness are prevalent features of cancer. While extensive research has characterized skeletal muscle wasting in cancer cachexia, limited studies have investigated how cardiac structure and function are affected by therapy-naive cancer. In cell-based models of orthotopic, syngeneic epithelial ovarian cancer (EOC) and pancreatic ductal adenocarcinoma (PDAC), and a patient-derived pancreatic xenograft model (PDX), we evaluated cardiac structure, function, and metabolism. Tumor-bearing mice showed cardiac atrophy and intrinsic systolic and diastolic dysfunction; associated with hypotension and exercise intolerance. In hearts of ovarian tumor-bearing mice, fatty acid-supported mitochondrial respiration decreased and carbohydrate-supported respiration increased, establishing a substrate shift in cardiac metabolism that is characteristic of heart failure. EOC decreased cytoskeletal and cardioprotective gene expression, which was paralleled by downregulation of transcription factors that regulate cardiomyocyte size and function. PDX tumors altered myosin heavy chain isoform expression - a molecular phenotype observed in heart failure. Markers of autophagy and ubiquitin-proteasome system were upregulated with cancer, providing evidence of catabolic signaling that promotes cardiac wasting. Together, metabolic stress, cardiac gene dysregulation, and upregulation of catabolic pathways contribute to cardiac atrophy and failure during cancer. Finally, we demonstrate that pathological cardiac remodeling is induced by human cancer, providing translational evidence of cancer-induced cardiomyopathy.

physiology↗