Myostatin/AKT/FOXO Signaling Is Altered in Human Non-Ischemic Dilated Cardiomyopathy

SIMPLE SUMMARY: Cardiac muscle-specific E3 ligases are enzymes that transfer ubiquitin to proteins to label them for protein degradation through the ubiquitin proteasome system. The E3 ligases MAFbx and MuRF1 are regulated by the myostatin/AKT/FOXO pathway that involves the molecules myostatin, AKT and the transcription factors FOXO1 and FOXO3. It is known that the expression of the two E3 ligases MAFbx and MuRF1 could be changed in cardiac diseases. The aim of this study was to clarify whether the myostatin/AKT/FOXO pathway as well as the expression of MAFbx and MuRF1 are changed in dilated cardiomyopathy of ischemic origin (IDCM) and dilated cardiomyopathy of non-ischemic origin (NIDCM) compared to a control group. MAFbx and transcription factor FOXO1 mRNA and protein expression as well as AKT mRNA and myostatin protein expression were decreased in patients with NIDCM compared to the control group. Apart from decreases of AKT and MAFbx mRNA expression, no significant differences were detected in patients with IDCM compared to the control group. Our results demonstrate that the myostatin/AKT/FOXO pathway is altered in patients with NIDCM, while patients with IDCM did not show substantial changes. The transcription factor FOXO1 seems to be an important drug target for regulating the expression of MAFbx in patients with NIDCM. 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.