Impaired insulin signaling accelerates cardiac mitochondrial dysfunction after myocardial infarction

Abstract

Diabetes increases mortality and accelerates left ventricular (LV) dysfunction following myocardial infarction (MI). This study sought to determine the impact of impaired myocardial insulin signaling, in the absence of diabetes, on the development of LV dysfunction following MI. Mice with cardiomyocyte-restricted knock out of the insulin receptor (CIRKO) and wild type (WT) mice were subjected to proximal left coronary artery ligation (MI) and followed for 14 days. Despite equivalent infarct size, mortality was increased in CIRKO-MI vs. WT-MI mice (68 % vs. 40 %, respectively). In surviving mice, LV ejection fraction and dP/dt were reduced by > 40% in CIRKO-MI vs. WT-MI. Relative to shams, isometric developed tension in LV papillary muscles increased in WT-MI but not in CIRKO-MI. Time to peak tension and relaxation times were prolonged in CIRKO-MI vs. WT-MI suggesting impaired, load-independent myocardial contractile function. To elucidate mechanisms for impaired LV contractility, mitochondrial function was examined in permeabilized cardiac fibers. Whereas maximal ADP-stimulated mitochondrial O 2 consumption rates (V ADP ) with palmitoyl carnitine were unchanged in WT-MI mice relative to sham-operated animals, V ADP was significantly reduced in CIRKO-MI (13.17 ± 0.94 vs. 9.14 ± 0.88 nmol O 2 /min/mgdw, p<0.05). Relative to WT-MI, expression levels of GLUT4, PPAR-α, SERCA2, and the FA-Oxidation genes MCAD, LCAD, CPT2 and the electron transfer flavoprotein ETFDH were repressed in CIRKO-MI. Thus reduced insulin action in cardiac myocytes accelerates post-MI LV dysfunction, due in part to a rapid decline in mitochondrial FA oxidative capacity, which combined with limited glucose transport capacity may reduce substrate utilization and availability.

Respirometric Oxidative Phosphorylation Assessment in Saponin-permeabilized Cardiac Fibers

“…Furthermore, RCR can be used as a quality assurance marker and can identify changes in coupling resulting from experimental or pathological interventions 5 . Well-coupled permeabilized murine cardiac preparations yield an RCR between 3-6 depending on the incubation solution utilized 1,8,9 .…”

Increased Protein Tyrosine Phosphatase 1B (PTP1B) Activity and Cardiac Insulin Resistance Precede Mitochondrial and Contractile Dysfunction in Pressure‐Overloaded Hearts

“…In the heart, deletion of the insulin receptor promotes oxidative stress and diminishes mitochondrial respiratory capacity 34. Consistently, cardiomyocyte‐specific loss of the insulin receptor accelerates cardiac mitochondrial dysfunction and thereby worsens left ventricular function and survival in mice with MI 5. Therefore, it is reasonable to postulate that the development of cIR in pressure‐overloaded hearts was an important trigger of mitochondrial dysfunction.…”

“…Studies in genetic models have shown that impaired cardiac insulin signaling has an adverse impact on mitochondrial and contractile function 5, 6. However, whether cardiac insulin action is affected in clinically relevant models of HF is unclear.…”

“…Notably, the reverse relationship may also exist, which applies particularly to the heart. For example, genetic deletion of cardiac insulin receptor accelerates mitochondrial dysfunction in myocardial infarction (MI) and diabetic cardiomyopathy 5, 6…”

GSK-3 protein and the heart: friend or foe?

“…(71,72) Recently, Sena et al (73) used cardiomyocyte-restricted insulin receptor knock out (CIRKO) mice to investigate possible mechanisms responsible for this. In a model of proximal coronary artery ligation to induce infarction, they followed changes in the heart over a 14 day period.…”