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Treatment with XMU-MP-1 erases hyperglycaemic memory in hearts of diabetic mice
Zhigang Zhang1, Yan-Fang Si2, Wenying Hu1
1Department of Cardiology, Putuo Center Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Abstract:
Hyperglycaemic memory refers to the damages occurred under early hyperglycaemic environment in organs of diabetic patients persisting after intensive glycaemic control. Mammalian sterile 20-like kinase 1 (Mst1) contributes to the development of diabetic cardiomyopathy. Here, we investigated the role of Mst1 in hyperglycaemic memory and test the effect of XMU-MP-1, a Mst1 inhibitor, on hyperglycaemic memory in hearts. Eight weeks after induction of type 1 diabetes by injection with streptozotocin (STZ) in mice, glycaemic control was obtained by means of insulin treatment and maintained for 4 additional weeks. In the diabetic mice, insulin treatment alone did not reduce phosphorylation of Mst1 or improve cardiac function. Treatment with XMU-MP-1 alone immediately after induction of diabetes for 12 weeks did not improve myocardial function in mice. But treatment with XMU-MP-1 for the later 4 weeks relieved myocardial dysfunction when glycaemic control was obtained by insulin treatment simultaneously. Mst1 deficiency and glycaemic control synergistically improved myocardial function and reduced apoptosis in myocardium of diabetic mice. Mechanistically, when Mst1 was deficient or inhibited by XMU-MP-1, AMPK was activated and mitochondrial dysfunction was attenuated. In vitro, treatment with AMPK activator reversed the detrimental effects of Mst1 overexpression in cultured cardiomyocytes. XMU-MP-1 might thus be envisaged as a complement for insulin treatment against diabetic cardiomyopathy.
Insights
Mammalian sterile 20-like kinase 1 (Mst1) inhibition, alongside insulin therapy, improves heart function in diabetic mice by mitigating hyperglycaemic memory. Mst1 inhibition activates AMPK and improves mitochondrial function, offering a potential complementary treatment for diabetic cardiomyopathy.
Area of Science:
- Cardiology
- Metabolism
- Molecular Biology
Background:
- Hyperglycaemic memory causes persistent organ damage in diabetes.
- Mammalian sterile 20-like kinase 1 (Mst1) is implicated in diabetic cardiomyopathy development.
- The role of Mst1 in hyperglycaemic memory requires further investigation.
Purpose of the Study:
- To investigate the role of Mst1 in hyperglycaemic memory.
- To evaluate the therapeutic effect of XMU-MP-1, an Mst1 inhibitor, on hyperglycaemic memory in the heart.
- To explore the underlying mechanisms of Mst1's action in diabetic cardiomyopathy.
Main Methods:
- Type 1 diabetes was induced in mice using streptozotocin (STZ).
- Glycaemic control was achieved with insulin treatment.
- Mice were treated with XMU-MP-1, an Mst1 inhibitor, during different phases of diabetes and treatment.
- Cardiac function, Mst1 phosphorylation, apoptosis, and AMPK activation were assessed.
- In vitro studies using cultured cardiomyocytes were performed.
Main Results:
- Insulin treatment alone did not improve cardiac function or reduce Mst1 phosphorylation in diabetic mice.
- Simultaneous treatment with XMU-MP-1 and insulin during the later stage of diabetes improved myocardial function.
- Mst1 deficiency or inhibition synergistically improved cardiac function and reduced myocardial apoptosis.
- Mst1 inhibition or deficiency led to AMPK activation and attenuated mitochondrial dysfunction.
- AMPK activation reversed detrimental effects of Mst1 overexpression in cardiomyocytes.
Conclusions:
- Mst1 plays a significant role in mediating hyperglycaemic memory-induced cardiac dysfunction.
- XMU-MP-1, as an Mst1 inhibitor, shows potential as a complementary therapy to insulin for treating diabetic cardiomyopathy.
- Targeting Mst1 and activating AMPK may represent a novel therapeutic strategy for diabetic heart disease.
