Glutamine Regulates Cardiac Progenitor Cell Metabolism and Proliferation.
Autologous transplantation of cardiac progenitor cells (CPCs) alleviates myocardial dysfunction in the damaged heart; however, the mechanisms that contribute to their reparative qualities remain poorly understood. In this study, we examined CPC metabolism to elucidate the metabolic pathways that regulate their proliferative capacity. In complete growth medium, undifferentiated CPCs isolated from adult mouse heart proliferated rapidly (Td  = 13.8 hours). CPCs expressed the Glut1 transporter and their glycolytic rate was increased by high extracellular glucose (Glc) concentration, in the absence of insulin. Although high Glc concentrations did not stimulate proliferation, glutamine (Gln) increased CPC doubling time and promoted survival under conditions of oxidative stress. In comparison with Glc, pyruvate (Pyr) or BSA-palmitate, Gln, when provided as the sole metabolic substrate, increased ATP-linked and uncoupled respiration. Although fatty acids were not used as respiratory substrates when present as a sole carbon source, Gln-induced respiration was doubled in the presence of BSA-palmitate, suggesting that Gln stimulates fatty acid oxidation. Additionally, Gln promoted rapid phosphorylation of the mTORC1 substrate, p70S6k, as well as retinoblastoma protein, followed by induction of cyclin D1 and cdk4. Inhibition of either mTORC1 or glutaminolysis was sufficient to diminish CPC proliferation, and provision of cell permeable α-ketoglutarate in the absence of Gln increased both respiration and cell proliferation, indicating a key role of Gln anaplerosis in cell growth. These findings suggest that Gln, by enhancing mitochondrial function and stimulating mTORC1, increases CPC proliferation, and that interventions to increase Gln uptake or oxidation may improve CPC therapy.
Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.|Department of Medicine, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky, USA.
Joshua K
JK
Salabei
Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.|Department of Medicine, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky, USA.
Pawel K
PK
Lorkiewicz
Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.|Department of Medicine, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky, USA.|Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky, USA.
Candice R
CR
Holden
Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
Qianhong
Q
Li
Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
Kyung U
KU
Hong
Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.|Department of Medicine, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky, USA.|Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky, USA.
Roberto
R
Bolli
Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.|Department of Medicine, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky, USA.|Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky, USA.|Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, USA.
Aruni
A
Bhatnagar
Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.|Department of Medicine, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky, USA.|Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky, USA.|Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, USA.
Bradford G
BG
Hill
D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology; D051379:Mice; D009124:Muscle Proteins / Q000096:biosynthesis; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
D009124:Muscle Proteins; D005973:Glutamine
Bioenergetics; Cell therapy; Heart failure; Mitochondria; Proliferation; Stem cells