Abstract
BackgroundThis study aimed to evaluate the efficacy of mesenchymal stem cell (MSC) transplantation to mitigate abnormalities in cardiac-specific and systemic metabolism mediated by a combination of a myocardial infarction and diet-induced insulin resistance.MethodsC57BL/6 mice were high-fat fed for eight weeks prior to induction of a myocardial infarction via chronic ligation of the left anterior descending coronary artery. MSCs were administered directly after myocardial infarction induction through a single intramyocardial injection. Echocardiography was performed prior to the myocardial infarction as well as seven and 28 days post-myocardial infarction. Hyperinsulinemic-euglycemic clamps coupled with 2-[14C]deoxyglucose were employed 36 days post-myocardial infarction (13 weeks of high-fat feeding) to assess systemic insulin sensitivity and insulin-mediated, tissue-specific glucose uptake in the conscious, unrestrained mouse. High-resolution respirometry was utilized to evaluate cardiac mitochondrial function in saponin-permeabilized cardiac fibers.ResultsMSC administration minimized the decline in ejection fraction following the myocardial infarction. The greater systolic function in MSC-treated mice was associated with increased in vivo cardiac glucose uptake and enhanced mitochondrial oxidative phosphorylation efficiency. MSC therapy promoted reductions in fasting arterial glucose and fatty acid concentrations. Additionally, glucose uptake in peripheral tissues including skeletal muscle and adipose tissue was elevated in MSC-treated mice. Enhanced glucose uptake in these tissues was associated with improved insulin signalling as assessed by Akt phosphorylation and prevention of a decline in GLUT4 often associated with high-fat feeding.ConclusionsThese studies provide insight into the utility of MSC transplantation as a metabolic therapy that extends beyond the heart exerting beneficial systemic effects on insulin action.
Highlights
This study aimed to evaluate the efficacy of mesenchymal stem cell (MSC) transplantation to mitigate abnormalities in cardiac-specific and systemic metabolism mediated by a combination of a myocardial infarction and diet-induced insulin resistance
Given the deleterious impact of insulin resistance on the infarcted heart, this study aimed to identify whether the efficacy of MSC administration to minimize alterations in metabolic processes that assist in ATP provision following a myocardial infarction (MI) is maintained in a murine model of diet-induced insulin resistance/MI
Measurement of body weight from one week prior to the ligation surgery to five weeks post-MI indicated that the MI + PBS mice were lower as a result of the MI (Figure 2e)
Summary
This study aimed to evaluate the efficacy of mesenchymal stem cell (MSC) transplantation to mitigate abnormalities in cardiac-specific and systemic metabolism mediated by a combination of a myocardial infarction and diet-induced insulin resistance. In the presence of poor cell survival and engraftment, the mechanisms promoting beneficial results reported following stem cell transplantation have been subject to an increasing number of studies that suggest cell-mediated paracrine effects are likely the major mediator for the improvement in cardiac function and the attenuation or slowing of the maladaptive processes [10]. In terms of cardiac metabolism, animal studies indicate the ability of stem cell transplantation, mesenchymal stem cell (MSC) transplantation, to lessen aberrations in glucose utilization, mitochondrial function and high-energy phosphate provision in the infarcted heart [14,15,16,17,18]. Individuals with insulin resistance and type 2 diabetes exhibit a greater probability of developing heart failure and higher mortality following a MI [22,24,25]
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