Mitochondrial integrity distinguishes exercise-induced vs. pathogenic cardiac hypertrophy

Cardiac hypertrophy is a consequence of exercise training, as well as certain cardiomyopathies. However, the key genetic drivers of cardiac remodeling in a healthy vs diseased heart are inadequately understood. Our purpose was to determine the genetic architecture of exercise training-induced cardiac remodeling and hypertrophy. The exercise hybrid mouse diversity panel (ExcHMDP) is comprised of 100 strains of Exc trained (TRN) and sedentary (SED) animals (n=4-8/strain/group). After 30d of exercise, running wheels were locked, and 24-hours post-exercise, 6h-fasted animals were euthanized and tissues harvested (~20 tissues/mouse). To interrogate pathogenic cardiac hypertrophy, isoproterenol (ISO, 30mg/kg/day for 21d) was administered to a second HMDP cohort, and similar to TRN hearts, RNAseq analyses were performed. TRN increased heart weight in 85 of 100 mouse strains vs. SED. Of the nearly thirty heart phenotypes assessed, none correlated significantly with running distance. Enrichment analysis of differential gene expression revealed mitochondrial function, inflammatory and immune processes, calcium signaling, muscle growth and development, and angiogenesis (FDR<0.05) as top pathways impacted by TRN. Biological processes divergent between the Exc and ISO-HMDPs included oxidative phosphorylation, electron transport chain, and mitochondrial respiratory chain complex assembly (FDR<1.1E-07). Electron microscopy analyses of TRN vs. ISO hearts showed differential remodeling of mitochondrial cristae involved in oxidative metabolism. Preliminary sex differences studies using an acute cardiac Esr1 (estrogen receptor alpha, ERa) knockout revealed reduced cardiac function, impaired mitochondrial metabolism, and extensive myocardial fibrosis in adult female C56Bl6/J mice (n=6); molecular assays revealed increased expression of alpha smooth muscle actin (P=0.002) and collagens Col1a2 and Col6a3 (P=0.02; P=0.006), suggesting that ERa may be a mediator of sex-specific cardiac remodeling. Our studies provide important insight into the genetic architecture of cardiac remodeling associated with healthy vs. pathogenic hypertrophy. A primary goal is that our transcriptomics analyses are leveraged to advance therapeutics to combat hypertrophic cardiac myopathy-associated heart failure. Funding: NIH U01 AG070959; U54DK120342 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.