Mesenchymal stem cell transplantation for the infarcted heart: a role in minimizing abnormalities in cardiac-specific energy metabolism

Abstract

Hughey CC, Johnsen VL, Ma L, James FD, Young PP, Wasserman DH, Rottman JN, Hittel DS, Shearer J. Mesenchymal stem cell transplantation for the infarcted heart: a role in minimizing abnormalities in cardiac-specific energy metabolism. Am J Physiol Endocrinol Metab 302: E163-E172, 2012. First published October 4, 2011; doi:10.1152/ajpendo.00443.2011.-Intense interest has been focused on cell-based therapy for the infarcted heart given that stem cells have exhibited the ability to reduce infarct size and mitigate cardiac dysfunction. Despite this, it is unknown whether mesenchymal stem cell (MSC) therapy can prevent metabolic remodeling following a myocardial infarction (MI). This study examines the ability of MSCs to rescue the infarcted heart from perturbed substrate uptake in vivo. C57BL/6 mice underwent chronic ligation of the left anterior descending coronary artery to induce a MI. Echocardiography was performed on conscious mice at baseline as well as 7 and 23 days post-MI. Twenty-eight days following the ligation procedure, hyperinsulinemic euglycemic clamps assessed in vivo insulin sensitivity. Isotopic tracer administration evaluated whole body, peripheral tissue, and cardiac-specific glucose and fatty acid utilization. To gain insight into the mechanisms by which MSCs modulate metabolism, mitochondrial function was assessed by high-resolution respirometry using permeabilized cardiac fibers. Data show that MSC transplantation preserves insulin-stimulated fatty acid uptake in the peri-infarct region (4.25 Ϯ 0.64 vs. 2.57 Ϯ 0.34 vs. 3.89 Ϯ 0.54 mol·100 g Ϫ1 ·min Ϫ1 , SHAM vs. MI ϩ PBS vs. MI ϩ MSC; P Ͻ 0.05) and prevents increases in glucose uptake in the remote left ventricle (3.11 Ϯ 0.43 vs. 3.81 Ϯ 0.79 vs. 6.36 Ϯ 1.08 mol·100 g Ϫ1 ·min Ϫ1 , SHAM vs. MI ϩ PBS vs. MI ϩ MSC; P Ͻ 0.05). This was associated with an enhanced efficiency of mitochondrial oxidative phosphorylation with a respiratory control ratio of 3.36 Ϯ 0.18 in MSC-treated cardiac fibers vs. 2.57 Ϯ 0.14 in the infarct-only fibers (P Ͻ 0.05). In conclusion, MSC therapy exhibits the potential to rescue the heart from metabolic aberrations following a MI. Restoration of metabolic flexibility is important given the metabolic demands of the heart and the role of energetics in the progression to heart failure. substrate uptake; mitochondria; hyperinsulinemic euglycemic clamp; skeletal muscle; peroxisome proliferator-activated receptor-␥ coactivator-1␣TO SATISFY THE CONTINUOUS ENERGETIC DEMAND of contractile function, fatty acids (FA) and to a lesser extent glucose are catabolized by mitochondria to synthesize ATP via oxidative phosphorylation (OXPHOS) (28). In response to physiological stressors, the heart must maintain an efficient means of energy provision. This is accomplished by the heart possessing metabolic flexibility, the ability to switch to the most appropriate substrate. Following a myocardial infarction (MI), the heart undergoes energetic alterations in which this adaptability is lost (14). This metabolic remodeling is characterized by a ...

Reduced expression of mitochondrial electron transport chain proteins from hibernating hearts relative to ischemic preconditioned hearts in the second window of protection

“…Several lines of evidence suggest that the mitochondrial proteome retains plasticity with strategies that might improve heart failure, as supported by an observed increase in the expression of mitochondrial ETC proteins following resynchronization of dogs with heart failure [27]. With the observations that cell-based therapies have promise in improving contractile function in patients with ischemic cardiomyopathy [28], their role in favorably altering energetic pathways that underlie mechanisms of heart failure are worth exploring [29]. Clearly, future studies should address whether additional interventions that could improve or retain the mitochondrial proteome could lead to a favorable effect on electron transport and maximal oxygen consumption.…”

Diminishing impairments in glucose uptake, mitochondrial content, and ADP-stimulated oxygen flux by mesenchymal stem cell therapy in the infarcted heart

“…In preparation for the hyperinsulinemic-euglycemic clamps (insulin clamps), the mice underwent chronic venous and arterial catheterization surgery 28 days postligation, as previously described (17). The mice were housed individually for 7 days postcatheterization to ensure the mice were within 10% of presurgical weight for use in the insulin clamps.…”

“…Plasma insulin was evaluated by a double antibody method, as previously performed (26). Plasma NEFAs (NEFA C kit; Wako Chemicals, Richmond, VA) and glucose were determined spectrophotometrically (Molecular Devices, Sunnyvale, CA), as previously described (17). Plasma 2-[ 14 C]DG was assessed as previously outlined (37).…”

“…10 mM cytochrome c were added to ensure the outer mitochondrial membrane was intact after processing. Following the respirometry studies, the fibers were stored at Ϫ80°C until use for citrate synthase activity determination as previously outlined (17).…”

“…1 Thirteen-week-old, male C57BL/6J mice (Jackson Laboratories, Bar Harbour, ME) were randomly separated into three groups: Sham, MI ϩ phosphate-buffered saline (MIϩPBS), and MI ϩ MSC (MIϩMSC). A left anterior descending coronary artery chronic ligation model was employed to induce a MI, as previously described (17). Immediately following the ligation, 25 l of PBS (pH 7.2) or 2.5 ϫ 10 5 MSCs in 25 l of PBS (pH 7.2) were administered via a single intramyocardial injection into the blanching peri-infarct area of the MIϩPBS or MIϩMSC mice, respectively.…”