Liraglutide combined with HIIT preserves contractile apparatus and blunts the progression of heart failure in diabetic cardiomyopathy rats

Liraglutide has been shown to alleviate heart failure in patients with type 2 diabetes. High-intensity interval training (HIIT) has also been proven to improve cardiac function in diabetes. The present study explored the effects and underlying mechanisms of liraglutide and HIIT combination therapy in alleviating diabetic cardiomyopathy (DCM). A high-fat diet and low-dose streptozotocin (STZ) were utilized to induce the DCM model. Eight weeks of liraglutide injection and HIIT were used to treat DCM. Subsequently, cardiac function, serum metabolic biomarkers, serum glucagon-like peptide-1 (GLP-1), histology examination, cardiac alpha-myosin heavy chain (α-MHC), and β-MHC messenger RNA (mRNA) expression, forkhead box protein O1 (FOXO1) and muscle-specific RING finger protein 1 (MURF1) mRNA expression and colocalization, and expression of GLP-1 and GLP-1 receptor (GLP-1R) proteins were detected after the intervention. Results showed that DCM rats developed hyperglycemia with eccentric hypertrophy, fibrosis, and reduced systolic and diastolic function. All interventions significantly reversed the development of heart failure by alleviating the disruption of contractile apparatus, reversed the adult α-MHC transformed to fetal β-MHC, and reduced FOXO1 and MURF1 mRNA expression. Combination therapy had a better effect in alleviating cardiac fibrosis, reducing cardiovascular risk biomarkers, controlling eccentric hypertrophy, and improving systolic function. Combination therapy significantly reduced FOXO1 and MURF1 colocalization and improved the GLP-1R sensitivity in diabetic hearts. Overall, these findings demonstrate that combination therapy can reverse cardiac failure in diabetic rats by controlling the degradation of contractile apparatus by downregulating the cardiac atrophy gene expression and interrupting their colocalization, as well as upregulating GLP-1 signaling.