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Published on: June 22, 2020
Myostatin/AKT/FOXO Signaling Is Altered in Human Non-Ischemic Dilated Cardiomyopathy
Lea Hildebrandt1, Maja-Theresa Dieterlen1, Kristin Klaeske1
1Department of Cardiac Surgery, Heart Center, HELIOS Clinic, University Hospital Leipzig, 04289 Leipzig, Germany.
Abstract:
Disturbances in the ubiquitin proteasome system, and especially changes of the E3 ligases, are subjects of interest when searching for causes and therapies for cardiomyopathies. The aim of this study was to clarify whether the myostatin/AKT/forkhead box O (FOXO) pathway, which regulates the expression of the E3 ligases muscle atrophy F-box gene (MAFbx) and muscle ring-finger protein-1 (MuRF1), is changed in dilated cardiomyopathy of ischemic origin (IDCM) and dilated cardiomyopathy of non-ischemic origin (NIDCM). The mRNA and protein expression of myostatin, AKT, FOXO1, FOXO3, MAFbx and MuRF1 were quantified by real-time polymerase chain reaction and ELISA, respectively, in myocardial tissue from 26 IDCM and 23 NIDCM patients. Septal tissue from 17 patients undergoing Morrow resection served as a control. MAFbx and FOXO1 mRNA and protein expression (all p < 0.05), AKT mRNA (p < 0.01) and myostatin protein expression (p = 0.02) were decreased in NIDCM patients compared to the control group. Apart from decreases of AKT and MAFbx mRNA expression (both p < 0.01), no significant differences were detected in IDCM patients compared to the control group. Our results demonstrate that the myostatin/AKT/FOXO pathway is altered in NIDCM but not in IDCM patients. FOXO1 seems to be an important drug target for regulating the expression of MAFbx in NIDCM patients.
Insights
The myostatin/AKT/forkhead box O (FOXO) pathway is altered in non-ischemic dilated cardiomyopathy (NIDCM) but not in ischemic dilated cardiomyopathy (IDCM). FOXO1 may be a therapeutic target for NIDCM by regulating muscle atrophy F-box gene (MAFbx) expression.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Ubiquitin proteasome system disturbances, particularly E3 ligase alterations, are implicated in cardiomyopathy pathogenesis and treatment.
- The myostatin/AKT/forkhead box O (FOXO) pathway influences E3 ligases, including muscle atrophy F-box gene (MAFbx) and muscle ring-finger protein-1 (MuRF1).
Purpose of the Study:
- To investigate alterations in the myostatin/AKT/FOXO pathway in ischemic dilated cardiomyopathy (IDCM) and non-ischemic dilated cardiomyopathy (NIDCM).
- To determine if the expression of myostatin, AKT, FOXO1, FOXO3, MAFbx, and MuRF1 differs between NIDCM, IDCM, and control groups.
Main Methods:
- Quantification of mRNA and protein expression using real-time polymerase chain reaction and ELISA.
- Analysis of myocardial tissue from 26 IDCM patients, 23 NIDCM patients, and 17 control subjects (Morrow resection septal tissue).
Main Results:
- In NIDCM patients, decreased mRNA and protein expression of MAFbx and FOXO1, decreased AKT mRNA, and decreased myostatin protein were observed compared to controls.
- IDCM patients showed decreased AKT and MAFbx mRNA expression but no other significant differences compared to controls.
- The myostatin/AKT/FOXO pathway was significantly altered in NIDCM but not in IDCM.
Conclusions:
- The myostatin/AKT/FOXO pathway is dysregulated in non-ischemic dilated cardiomyopathy.
- FOXO1 emerges as a potential therapeutic target for managing MAFbx expression in NIDCM.
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