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Chicago Ridge, IL, United States

Roberts N.W.,University of Illinois at Chicago | Gonzalez-Vega M.,University of Illinois at Chicago | Berhanu T.K.,University of Illinois at Chicago | Mull A.,University of Illinois at Chicago | And 4 more authors.
Cardiovascular Diabetology | Year: 2015

Background: Cardiomyopathy is a devastating complication of obesity and type 2 diabetes mellitus (T2DM). It arises even in patients with normoglycemia (glycosylated hemoglobin, A1C ≤7 %). As obesity and T2DM are approaching epidemic levels worldwide, the cardiomyopathy associated with these diseases must be therapeutically addressed. We have recently analyzed the systemic effects of a 12-week high fat diet (HFD) on wild type mice from the C57Bl/6 (B6) strain and the wild type super-healing Murphy Roths Large (MRL) mouse strain. The MRL HFD mice gained significantly more weight than their control diet counterparts, but did not present any of the other usual systemic T2DM phenotypes. Methods: Cardiac pathology and adaptation to HFD-induced obesity in the MRL mouse strain compared to the HFD C57Bl/6 mice were thoroughly analyzed with echocardiography, histology, qPCR, electron microscopy and immunoblots. Results: The obese HFD C57Bl/6 mice develop cardiac hypertrophy, cardiomyocyte lipid droplets, and initiate an ineffective metabolic adaptation of an overall increase in electron transport chain complexes. In contrast, the obese HFD MRL hearts do not display hypertrophy nor lipid droplets and their metabolism adapts quite robustly by decreasing pAMPK levels, decreasing proteins in the carbohydrate metabolism pathway and increasing proteins utilized in the β-oxidation pathway. The result of these metabolic shifts is the reduction of toxic lipid deposits and reactive oxygen species in the hearts of the obese HFD fed MRL hearts. Conclusions: We have identified changes in metabolic signaling in obese HFD fed MRL mice that confer resistance to diabetic cardiomyopathy. The changes include a reduction of cardiac pAMPK, Glut4 and hexokinase2 in the MRL HFD hearts. Overall the MRL hearts down regulate glucose metabolism and favor lipid metabolism. These adaptations are essential to pursue for the identification of novel therapeutic targets to combat obesity related cardiomyopathy. © 2015 Roberts et al. Source

Grajales L.,the Center for Cardiovascular Research | Garcia J.,the Center for Cardiovascular Research | Banach K.,the Center for Cardiovascular Research | Geenen D.L.,the Center for Cardiovascular Research
Journal of Molecular and Cellular Cardiology | Year: 2010

Bone marrow-derived mesenchymal stem cells (BM-MSCs) can be induced to differentiate into myogenic cells. Despite their potential, previous studies have not been successful in producing a high percentage of cardiac-like cells with a muscle phenotype. We hypothesized that cardiac lineage development in BM-MSC is related to cell passage, culture milieu, and enrichment for specific cell subtypes before and during differentiation. Our study demonstrated that Lin- BM-MSC at an intermediate passage (IP; P8-P12) expressed cardiac troponin T (cTnT) after 21 days in culture. Cardiac TnT expression was similar whether IP cells were differentiated in media containing 5-azacytidine + 2% FBS (AZA; 14%) or 2% FBS alone (LS; 12%) and both were significantly higher than AZA + 5% FBS. This expression was potentiated by first enriching for CD117/Sca-1 cells followed by differentiation (AZA, 39% and LS, 28%). A second sequential enrichment for the dihydropyridine receptor subunit α2δ1 (DHPR-α2) resulted in cardiac TnT expressed in 54% of cultured cells compared to 28% of cells after CD117/Sca-1+ enrichment. Cells enriched for CD117/Sca-1 and subjected to differentiation displayed spontaneous intracellular Ca2+ transients with an increase in transient frequency and a 60% decrease in the transient duration amplitude between days 14 and 29. In conclusion, IP CD117/Sca-1+ murine BM-MSCs display robust cardiac muscle lineage development that can be induced independent of AZA but is diminished under higher serum concentrations. Furthermore, temporal changes in calcium kinetics commensurate with increased cTnT expression suggest progressive maturation of a cardiac muscle lineage. Enrichment with CD117/Sca-1 to establish lineage commitment followed by DHPR-α2 in lineage developing cells may enhance the therapeutic potential of these cells for transplantation. © 2009 Elsevier Ltd. All rights reserved. Source

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