Plain Language Summary
Rat study demonstrating that MOTS-c and aerobic exercise training both independently induce cardiac physiological hypertrophy and improve cardiac function through a common NRG1/ErbB4/C/EBPβ signaling mechanism, with MOTS-c replicating key aspects of exercise-induced beneficial cardiac remodeling. Identifies NRG1 pathway activation as a shared mechanism between MOTS-c and exercise in the heart. Establishes that MOTS-c mimics exercise-induced cardioprotective signaling through NRG1/ErbB4—the neuregulin pathway that drives physiological rather than pathological cardiac hypertrophy—providing mechanistic evidence for MOTS-c as a pharmacological substitute for the beneficial cardiac adaptations to aerobic training.
Abstract
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 β (C/EBPβ) 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/EBPβ, 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/dt(p < 0.001, p < 0.001, p = 0.039) and dP/dt(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/EBPβ 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/EBPβ 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/EBPβ 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/EBPβ pathway.
Authors
Yuan, Jinghan; Xu, Bowen; Ma, Jiacheng; Pang, Xiaoli; Fu, Yu; Liang, Min; Wang, Manda; Pan, Yanrong; Duan, Yimei; Tang, Mi; Zhu, Bingmei; Laher, Ismail; Li, Shunchang