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MOTS-c repairs myocardial damage by inhibiting the CCN1/ERK1/2/EGR1 pathway in diabetic rats
Manda Wang1, Gangqiang Wang2, Xiaoli Pang1
1Institute of Sports Medicine and Health, Chengdu Sport University, Chengdu, China.
Abstract:
Cardiac structure remodeling and dysfunction are common complications of diabetes, often leading to serious cardiovascular events. MOTS-c, a mitochondria-derived peptide, regulates metabolic homeostasis by accelerating glucose uptake and improving insulin sensitivity. Plasma levels of MOTS-c are decreased in patients with diabetes. MOTS-c can improve vascular endothelial function, making it a novel therapeutic target for the cardiovascular complications of diabetes. We investigated the effects of MOTS-c on cardiac structure and function and analyzed transcriptomic characteristics in diabetic rats. Our results indicate that treatment with MOTS-c for 8-week repaired myocardial mitochondrial damage and preserved cardiac systolic and diastolic function. Transcriptomic analysis revealed that MOTS-c altered 47 disease causing genes. Functional enrichment analysis indicated MOTS-c attenuated diabetic heart disease involved apoptosis, immunoregulation, angiogenesis and fatty acid metabolism. Moreover, MOTS-c reduced myocardial apoptosis by downregulating CCN1 genes and thereby inhibiting the activation of ERK1/2 and the expression of its downstream EGR1 gene. Our findings identify potential therapeutic targets for the treatment of T2D and diabetic cardiomyopathy.
Insights
Mitochondria-derived peptide MOTS-c (Mitochondria Open Reading Frame 9-coding sequence) repaired heart damage and improved function in diabetic rats. This peptide shows promise for treating type 2 diabetes and diabetic cardiomyopathy.
Area of Science:
- Cardiology
- Metabolic Diseases
- Mitochondrial Biology
Background:
- Diabetes mellitus is a leading cause of cardiovascular complications, including cardiac structure remodeling and dysfunction.
- Mitochondria-derived peptide C (MOTS-c) is crucial for metabolic homeostasis, with decreased levels observed in diabetic patients.
- MOTS-c demonstrates potential in improving vascular endothelial function, suggesting it as a therapeutic target for diabetic cardiovascular complications.
Purpose of the Study:
- To investigate the therapeutic effects of MOTS-c on cardiac structure and function in a rat model of type 2 diabetes.
- To analyze the transcriptomic changes induced by MOTS-c treatment in the diabetic heart.
- To identify molecular mechanisms underlying MOTS-c's protective effects against diabetic cardiomyopathy.
Main Methods:
- Diabetic rats were treated with MOTS-c for 8 weeks.
- Cardiac structure and function were assessed.
- Transcriptomic analysis was performed to identify gene expression alterations.
- Functional enrichment analysis was conducted to understand the biological pathways affected by MOTS-c.
Main Results:
- MOTS-c treatment repaired myocardial mitochondrial damage and preserved cardiac systolic and diastolic function in diabetic rats.
- Transcriptomic analysis revealed that MOTS-c modulated 47 disease-associated genes.
- Functional enrichment analysis indicated that MOTS-c attenuated pathways involved in apoptosis, immunoregulation, angiogenesis, and fatty acid metabolism in the diabetic heart.
- Specifically, MOTS-c reduced myocardial apoptosis by downregulating CCN1, inhibiting ERK1/2 activation, and decreasing EGR1 expression.
Conclusions:
- MOTS-c effectively ameliorates cardiac damage and dysfunction in type 2 diabetes.
- MOTS-c exerts protective effects by modulating key molecular pathways, including apoptosis and metabolic processes.
- MOTS-c represents a promising therapeutic candidate for treating type 2 diabetes and its associated diabetic cardiomyopathy.
