The role of cardiac O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) transferase (OGT) on endurance capacity and physical activity (LB681)

Abstract

The cardiovascular benefits obtained from endurance exercise are well established. Physiological cardiac hypertrophy occurs in response to the beneficial stress of exercise at both the cellular and transcriptional levels. The mechanisms triggering cardiac remodeling to induce a physiological or pathological hypertrophic phenotype remain largely unknown. The posttranslational attachment of O‐Linked β‐N‐acetylglucosamine (O‐GlcNAc) to serine or threonine residues of proteins is catalyzed by O‐GlcNAc transferase (OGT). O‐GlcNAcylation is an important mediator of signal transduction and protein‐protein interactions. However, the relevance of elevated O‐GlcNAc levels in the heart is complex as it is implicated in both cardiac dysfunction, and cardioprotection. Preliminary data and recent literature also suggests that inducible cardiomyocyte‐specific knockdown of OGT (OGT‐KD) alters gene transcription, which results in a heart failure phenotype. We investigated the impact of inducible, cardiomyocyte‐specific OGT‐KD on exercise capacity in a mouse model. Ten week old OGT‐KD mice were randomly assigned to a one‐time run to exhaustion treadmill (TM) cohort, or a 4 week voluntary wheel running (WR) cohort, or appropriate control groups. The TM cohort tolerated a decreased workload overall and exhibited increased ventricular heart weight with an increase in the ratio of heart weight (HW) to tibia length (TL). OGT‐KD mice in the WR cohort had decreased body weight, decreased overall activity, and increased HW:TL. These data suggest that inducible cardiac‐specific OGT‐KD in a mouse model significantly decreases endurance capacity and physical activity, while causing hypertrophy of the heart muscle as early as 11 weeks of age.Grant Funding Source: NIH/NHLBI HL104549