The role of MOTS-c-mediated antioxidant defense in aerobic exercise alleviating diabetic myocardial injury.

Myocardial remodeling and dysfunction are commonly observed in type 2 diabetes mellitus (T2DM). Aerobic exercise can partly alleviate diabetes-induced myocardial dysfunction through its antioxidant actions. MOTS-c is a potential exercise mimic. This study aimed to investigate the effects of MOTS-c on improving diabetic heart function and its mechanism and to identify whether MOTS-c improved antioxidant defenses due to aerobic exercise. Herein, we established a rat model of T2DM induced by high-fat diet combined with a low-dose streptozotocin injection. Interventions were performed using intraperitoneal injections of MOTS-c (i.p. 0.5 mg/kg/day, 7 days/week) or aerobic exercise training (treadmill, 20 m/min, 60 min/day, 5 days/week) for 8 weeks. Myocardial ultrastructure was assessed using transmission electron microscopy (TEM), myocardial lipid peroxidation levels (MDA), superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) levels were assessed using colorimetric methods, and molecular analyses including MOTS-c, Kelch-like ECH-associated protein 1 (Keap1), Nuclear factor E2-related factor 2 (Nrf2), adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)and phospho-AMPK (p-AMPK) were examined using Western blot. The results showed that MOTS-c, with or without exercise, reduced myocardial ultrastructural damage and improved glucolipid metabolism and cardiac function in T2DM. Furthermore, MOTS-c increased antioxidant markers such as SOD, CAT, and the protein expression of myocardial MOTS-c, Keap1, Nrf2, and p-AMPK. MOTS-c with exercise treatment reduced myocardial MDA and increased p-AMPK significantly comparing to only exercise or MOTS-c alone. Our findings suggest that MOTS-c may be a helpful supplement for overcoming exercise insufficiency and improving myocardial structure and function in diabetes.

MOTS-c and aerobic exercise induce cardiac physiological adaptation via NRG1/ErbB4/CEBPß modification in rats.

AIMS: To determine the effects of the mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) and aerobic exercise on cardiac structure and function and explore the role of neuregulin-1 (NRG1)- ErbB2 receptor tyrosine kinase 4(ErbB4)- CCAAT-enhancer binding protein ß (C/EBPß) in cardiac physiological adaptation induced by MOTS-c and aerobic training. MAIN METHODS: We used Hematoxylin-Eosin staining(HE)and Transmission Electron Microscope (TEM) to observe the cardiac myocardial structure, carotid artery catheterization to test cardiac function, and real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting to describe the changes of NRG1, ErbB4, C/EBPß, and Gata in cardiac physiological adaptation. KEY FINDINGS: MOTS-c and aerobic training significantly increased heart weight and heart weight index (HWI) (all p < 0.05). Aerobic exercise and MOTS-c treatment thickened myocardial fibers, with a tendency of hypertrophy. Heart rate (HR) (p < 0.001, p = 0.010, p = 0.011), the isovolumic diastolic time constant (Tau) (p < 0.001, p < 0.001, p < 0.001) in exercised (E), MOST-c treated (M) and their combination (ME) decreased significantly, while the dP/dtmax (p < 0.001, p < 0.001, p = 0.039) and dP/dtmin (p < 0.001, p < 0.001, p = 0.001) in groups E, M and ME were significantly higher than those in group C, but EDP (p = 0.903, p = 0.708, p = 0.744) remained unchanged. Moreover, C/EBPß gene levels were significantly decreased in the differential gene expression between groups C and M transcriptomics sequencing. The levels of ErbB4 mRNA (p < 0.001, p < 0.001, p < 0.001) and Gata4 mRNA (p < 0.001, p < 0.001, p = 0.001) in groups E, M and ME increased significantly, while C/EBPß mRNA expression decreased significantly (p < 0.001, p = 0.002, p = 0.001), which was consistent with the results of transcriptome sequencing. NRG1 mRNA in group E was significantly higher than that in group C (p = 0.003), but there was no significant difference between groups M and ME (p = 0.804, p = 0.320). The protein expression of NRG1 (p = 0.026, p < 0.001, p < 0.001), ErbB4 (p < 0.001, p < 0.001, p < 0.001) and Gata4 (p = 0.014, p < 0.001, p = 0.006) in groups E, M and ME increased significantly, while C/EBPß decreased significantly (p < 0.001, p = 0.001, p = 0.002). SIGNIFICANCE: Our findings suggest that MOTS-c and aerobic exercise had similar effects, improving myocardial morphology and structure and enhancing cardiac function through activation of the NRG1-ErbB4-C/EBPß pathway.

The mitochondrial signaling peptide MOTS-c improves myocardial performance during exercise training in rats.

Cardiac remodeling is a physiological adaptation to aerobic exercise and which is characterized by increases in ventricular volume and the number of cardiomyocytes. The mitochondrial derived peptide MOTS-c functions as an important regulator in physical capacity and performance. Exercise elevates levels of endogenous MOTS-c in circulation and in myocardium, while MOTS-c can significantly enhance exercise capacity. However, the effects of aerobic exercise combined with MOTS-c on cardiac structure and function are unclear. We used pressure-volume conductance catheter technique to examine cardiac function in exercised rats with and without treatment with MOTS-c. Surprisingly, MOTS-c improved myocardial mechanical efficiency, enhanced cardiac systolic function, and had a tendency to improve the diastolic function. The findings suggest that using exercise supplements could be used to modulate the cardiovascular benefits of athletic training.