Author + information
- 1Department of Cardiology, Xijing Hospital, Fourth Military Medical University
- 2Department of Physiology, Basic Medical Science School, Fourth Military Medical University
- 3Department of Geriatrics, Xijing Hospital, Fourth Military Medical University
- 4Emergency Medicine Department, Thomas Jefferson University
Cardiac energy metabolic disorders majorly contribute to heart failure (HF) progression following myocardial infarction (MI). We have previously shown that branched chain amino acid (BCAA) catabolism is obviously impaired in the mitochondrion isolated from the MI-induced failing heart. However, the role of cardiac BCAA catabolic defects in heart failure remain largely unknown.
MI was induced by coronary artery ligation in a mouse model of defective BCAA catabolism (protein phosphatase-2Cm [PP2Cm] knockout [KO]) or in wild type (WT) mice. Primary cardiomyocytes were isolated from KO or WT heart. Cardiac function and structure were analyzed respectively by echocardiography or masson trichrome staining at 4 weeks post-MI.
Compared with WT group, MI-induced cardiac dysfunction and remodeling were obviously exacerbated in KO mice. In KO heart, chronic BCAA accumulation obviously suppressed cardiac glucose and lipid metabolism through inhibition of mitochondrial pyruvate dehydrogenase (PDH) and carnitine palmitoyltransferase-1 (CPT-1) activity. Furthermore, we found that defective BCAA catabolism caused succinyl-coenzyme A (succi-coA) accumulation, leading to excessive PDH and CPT-1 lysine succinylation and inactivation in the mitochondrion. Promoting cardiac BCAA catabolism or normalizing PDH and CPT-1 hyper-succinylation by SIRT5 (the specific desuccinylation enzyme) overexpression in the KO heart rescued metabolic, functional, and structural outcomes following MI.
The present study revealed a novel and crucial role of BCAA catabolism in the regulation of cardiac metabolism and stress response during HF progression following MI. These observations also for the first time provided direct evidence demonstrating that impaired BCAA catabolism-induced mitochondrial metabolic enzyme hyper-succinylation majorly contributes to energy metabolic disorders in MI-induced failing heart. Targeting defective BCAA catabolism or excessive mitochondrial metabolic enzyme lysine succinylation may be novel therapeutic strategies for post-MI HF management.