Scientific reports

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.

BPC 157-activated endothelial nitric oxide synthase (eNOS) is associated with tissue repair and angiogenesis as reported in previous studies. However, how BPC 157 regulates the vasomotor tone and intracellular Src-Caveolin-1 (Cav-1)-eNOS signaling is not yet clear. The present study demonstrated a concentration-dependent vasodilation effect of BPC 157 in isolated rat aorta. Attenuation of this vasodilation effect in the absence of endothelium suggested an endothelium-dependent vasodilation effect of BPC 157. Although slightly increased vasorelaxation in aorta without endothelium was noticed at high concentration of BPC 157, there was no direct relaxation effect on three-dimensional model made of vascular smooth muscle cells. The vasodilation effect of BPC 157 was nitric oxide mediated because the addition of L-NAME or hemoglobin inhibited the vasodilation of aorta. Nitric oxide generation was induced by BPC 157 as detected by intracellular DFA-FM DA labeling which was capable of promoting the migration of vascular endothelial cells. BPC 157 enhanced the phosphorylation of Src, Cav-1 and eNOS which was abolished by pretreatment with Src inhibitor, confirming the upstream role of Src in this signal pathway. Activation of eNOS required the released binding with Cav-1 in advance. Co-immunoprecipitation analysis revealed that BPC 157 could reduce the binding between Cav-1 and eNOS. Together, the present study demonstrates that BPC 157 can modulate the vasomotor tone of an isolated aorta in a concentration- and nitric oxide-dependent manner. BPC 157 can induce nitric oxide generation likely through the activation of Src-Cav-1-eNOS pathway.