Lysine Lactylation Modifies Cryab-Hspa1b Interactions and Prevents MAPK Signaling to Slow Diabetic Cardiomyopathy Progression

Abstract

Protein posttranslational modifications, including lactylation, have been intimately associated with myocardial energy metabolism. In this study, we investigated the role of Cryab in diabetic cardiomyopathy (DbCM) and its lysine lactylation (Kla). A spontaneous DbCM mouse model in db/db mice and a high-fat diet combined with i.p. streptozotocin injection mouse model were used. Primary cardiomyocytes were subjected to liposome-mediated transfection, followed by exposure to high glucose and palmitate. Cryab exhibited reduced Kla modification in myocardial tissue from DbCM mouse models and in damaged cardiomyocytes, while protein expression remained unchanged. Kla modification site mutation at K90R worsened cardiac systolic and diastolic dysfunction, myocardial hypertrophy, fibrosis, and apoptosis in vivo and in vitro. Cryab modulated the Hspa1b protein in a Kla-dependent manner and enhanced the stability of the Hspa1b protein. In DbCM mouse models or cardiomyocytes, Hspa1b protein expression was reduced, and the MAPK pathway was activated, which was further exacerbated following mutation at K90R. These findings demonstrate that reduced Kla modification in Cryab accelerated degradation of Hspa1b and activation of the MAPK pathway, thereby contributing to cardiac dysfunction associated with DbCM. These findings suggest that novel therapeutic strategies targeting protein Kla modification could be significant in the clinical management of DbCM. Article Highlights Cryab lysine lactylation (Kla) modification in myocardial tissue is reduced in db/db mice with diabetic cardiomyopathy (DbCM). Mutations in the Cryab Kla site exacerbate DbCM damage in vivo and in vitro. Cryab Kla enhances the stability of the Hspa1b protein by interacting with Hspa1b. Cryab blocks DbCM-induced MAPK signaling in an Hspa1b-dependent manner. Cryab/Hspa1b/MAPK signaling influences DbCM-associated cardiac dysfunction.