Integrative Investigation of Lactylome-Proteome Interplay in Diabetic Cardiomyopathy for Pinpointing Disease...

Lysine lactylation (Kla) has emerged as a novel posttranslational modification implicated in various disease processes, yet its role in diabetic cardiomyopathy (DCM) pathogenesis remains unknown. The objective of this study was to ascertain whether protein lactylation is involved in DCM progression.

Proteomic and lactate analysis via liquid chromatography with tandem mass spectrometry was performed on the heart tissues of db/m mice (as the control group) and db/db mice (as the DCM group). Subsequently, a series of bioinformatics analyses was employed to analyze the Kla site and Kla-modified proteins in the two groups.

Bioinformatics analysis revealed a greater abundance of Kla sites in the DCM group than in the control group. In addition, subcellular localization analysis indicated that Kla-modified proteins were predominantly located in the cytoplasm and mitochondria. Protein lactylation modification mainly occurred on histone H2, and in comparison to the control group, modification of the H4C1-K32 site was notably elevated in the DCM group. Furthermore, 113 significantly modified Kla sites were associated with 78 modified proteins in the DCM group, whereas 37 significantly modified Kla sites were associated with 25 modified proteins in the control group. These Kla-modified proteins participated in biological processes and pathways related to glucose metabolism and DCM. Finally, five candidate sites were identified using random forest, LASSO regression, support vector machine-recursive feature elimination, and logistic regression: A2ASS6_K928_Ttn, A2ASS6_K13499_Ttn, Q61425_K212_Hadh, Q8K2B3_K517_Sdha, and Q9R0Y5_K100_Ak1.

Our findings suggest that protein lactate modification in the lactylome and proteome could be a promising treatment for DCM. This provides a reliable basis for further investigating the roles of Kla and Kla-modified proteins to develop new and effective therapeutic targets for treating DCM.