Mots-c Attenuates Myocardial Mitochondrial Damage Through Inhibition Of Ccn1/erk1/2/egr1 Pathway

Mitochondrial dysfunction is considered as a major contributor to cardiac systolic and diastolic dysfunction in diabetes. As a newly identified mitochondria derived peptide, MOTS-c plays a vital role in the regulation of metabolic homeostasis and was shown to be closely related to type 2 diabetes (T2D). We hypothesized that MOTS-c could prevent myocardial mitochondrial damage and improve cardiac structure and function in T2D. PURPOSE: To explored the effects and molecular mechanisms of MOTS-c on mitochondrial damage and cardiac dysfunction in diabetes. METHODS: Thirty male Sprague Dawley rats were randomly divided into three groups: control (C, n = 10), diabetes (D, n = 10) and diabetes plus MOTS-c treatment (DM, n = 10). Diabetic rats induced by high-fat high-sugar diet combined with a low-dose streptozotocin (30 mg/kg) injection. Rats in DM group were injected with MOTS-c at a dose of 0.5 mg/kg/day and 7 days/week for 8 weeks. Echocardiography was used to measured cardiac systolic and diastolic function, and transmission electron microscopy (TEM) was used to observed myocardial ultrastructure. RNA sequencing was used to determin differentially expressed genes (DEGs). Gene Ontology (GO) were selected for functional enrichment analysis to screen out the related pathways and genes, and qRT-PCR was used to measure the mRNA expression levels of CCN1, ERK1/2 and EGR1. RESULTS: MOTS-c treatment significantly prevented mitochondrial swelling and vacuoles and repaired the disorder of myocardial fiber arrangement. There was no significant differences in ejection fraction (EF), E-wave peak, A-wave peak and E/A ratio between DM and C groups (all p > 0.05). 8-week MOTS-c treatment altered 47 causative genes in myocardium of diabetic rats. The results of GO enrichment analysis showed that CCN1 and EGR1 were highly expressed and appeared in the apoptosis related terms. CCN1 was included in the ERK1/2 cascade with the highest significance. The mRNA expression of CCN1, ERK2 and EGR1 were significantly decreased after MOTS-c treatment (p < 0.01). CONCLUSIONS: MOTS-c improves myocardial mitochondrial damage and attenuates the cardiac pathological remodeling and dysfunction. CCN1/ERK1/2/EGR1 pathway may play an important role in MOTS-c preventing myocardial damage in diabetes.