Modulation of Cardiac Sarcomeric Function in Mouse Models of Hyperglycemia

Abstract

Diabetes is a major risk factor for developing heart failure (HF) and patients with diabetes and HF have worse outcomes than patients with HF alone. Given that diabetes is associated with multiple metabolic impairments, it is critical to determine the mechanisms that exacerbate and worsen cardiac outcomes. Hyperglycemia has been associated with cardiac diastolic dysfunction, which is characterized by prolonged relaxation. The specific mechanisms underlying hyperglycemia-induced diastolic dysfunction are unclear. It is known that hyperglycemia induces profound perturbations in cardiac metabolism modifying acyl-based post-translational modifications (PTMs), which are a class of PTMs that have been gaining increasing focus as modulators of non-genomic protein function. We hypothesize that hyperglycemia contributes to cardiac dysfunction by modulating acyl-based modifications on sarcomeric proteins; thereby, leading to prolonged myofilament relaxation. We evaluated sarcomeric function and specific PTMs (acetylation, crotonylation, malonylation, propionylation, and hydoxy-butyrylation) on sarcomeric proteins in two mouse models that have elevated glucose without hyperinsulinemia: mice with inducible deletion of beta islet glucokinase and mice treated with streptozotocin (STZ) induced damage of the beta islet cells. In male and female mice of both models, myofibrils isolated from the hearts of animals with hyperglycemia demonstrated prolonged sarcomeric relaxation compared to myofibrils isolated from euglycemic mice. We found that sarcomeric proteins isolated from the hearts of hyperglycemic mice from both models have decreased protein acetylation. While crotonylation, malonylation, propionylation, and hydoxy-butyrylation are not different between hyperglycemic and euglycemic mice. To determine how decreased acetylation impacts sarcomeric mechanical function, myofibrils isolated from male and female euglycemic mice were treated with histone deacetylases decrease acetylation and mechanics were assessed. We found that decreased acetylation of myofibrils leads to prolonged relaxation similar to what was observed in hyperglycemic hearts. These findings indicate that specific modifications of acyl-PTMs on sarcomeric proteins modulate sarcomeric function and may contribute to overall diastolic dysfunction observed in hyperglycemia. This work was supported by the National Institutes of Health [K01AG066845 KCW] the American Heart Association [22CDA937598 KCW] and the University of Colorado Anschutz Medical Campus Ludeman Family Center for Women’s Health and Specialized Center for Research Excellence (SCORE) pilot award [KCW], Colorado Diabetes Research Center Pilot and Feasibility Award [P30DK11607 KCW)]. This is the full abstract presented at the American Physiology Summit 2024 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.