Developmental enhancement of adenylate kinase-AMPK metabolic signaling axis supports stem cell cardiac differentiation.
Energetic and metabolic circuits that orchestrate cell differentiation are largely unknown. Adenylate kinase (AK) and associated AMP-activated protein kinase (AMPK) constitute a major metabolic signaling axis, yet the role of this system in guiding differentiation and lineage specification remains u...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-04-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3083437?pdf=render |
| _version_ | 1818470602626826240 |
|---|---|
| author | Petras P Dzeja Susan Chung Randolph S Faustino Atta Behfar Andre Terzic |
| author_facet | Petras P Dzeja Susan Chung Randolph S Faustino Atta Behfar Andre Terzic |
| author_sort | Petras P Dzeja |
| collection | DOAJ |
| description | Energetic and metabolic circuits that orchestrate cell differentiation are largely unknown. Adenylate kinase (AK) and associated AMP-activated protein kinase (AMPK) constitute a major metabolic signaling axis, yet the role of this system in guiding differentiation and lineage specification remains undefined.Cardiac stem cell differentiation is the earliest event in organogenesis, and a suitable model of developmental bioenergetics. Molecular profiling of embryonic stem cells during cardiogenesis revealed here a distinct expression pattern of adenylate kinase and AMPK genes that encode the AK-AMP-AMPK metabolic surveillance axis. Cardiac differentiation upregulated cytosolic AK1 isoform, doubled AMP-generating adenylate kinase activity, and increased AMP/ATP ratio. At cell cycle initiation, AK1 translocated into the nucleus and associated with centromeres during energy-consuming metaphase. Concomitantly, the cardiac AMP-signal receptor AMPKα2 was upregulated and redistributed to the nuclear compartment as signaling-competent phosphorylated p-AMPKα(Thr172). The cardiogenic growth factor TGF-β promoted AK1 expression, while knockdown of AK1, AK2 and AK5 activities with siRNA or suppression by hyperglycemia disrupted cardiogenesis compromising mitochondrial and myofibrillar network formation and contractile performance. Induction of creatine kinase, the alternate phosphotransfer pathway, compensated for adenylate kinase-dependent energetic deficits.Developmental deployment and upregulation of the adenylate kinase/AMPK tandem provides a nucleocytosolic energetic and metabolic signaling vector integral to execution of stem cell cardiac differentiation. Targeted redistribution of the adenylate kinase-AMPK circuit associated with cell cycle and asymmetric cell division uncovers a regulator for cardiogenesis and heart tissue regeneration. |
| first_indexed | 2024-04-13T21:39:11Z |
| format | Article |
| id | doaj.art-b92a2878f2c34e94bb13f9bb1eb0d960 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T21:39:11Z |
| publishDate | 2011-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b92a2878f2c34e94bb13f9bb1eb0d9602022-12-22T02:28:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-04-0164e1930010.1371/journal.pone.0019300Developmental enhancement of adenylate kinase-AMPK metabolic signaling axis supports stem cell cardiac differentiation.Petras P DzejaSusan ChungRandolph S FaustinoAtta BehfarAndre TerzicEnergetic and metabolic circuits that orchestrate cell differentiation are largely unknown. Adenylate kinase (AK) and associated AMP-activated protein kinase (AMPK) constitute a major metabolic signaling axis, yet the role of this system in guiding differentiation and lineage specification remains undefined.Cardiac stem cell differentiation is the earliest event in organogenesis, and a suitable model of developmental bioenergetics. Molecular profiling of embryonic stem cells during cardiogenesis revealed here a distinct expression pattern of adenylate kinase and AMPK genes that encode the AK-AMP-AMPK metabolic surveillance axis. Cardiac differentiation upregulated cytosolic AK1 isoform, doubled AMP-generating adenylate kinase activity, and increased AMP/ATP ratio. At cell cycle initiation, AK1 translocated into the nucleus and associated with centromeres during energy-consuming metaphase. Concomitantly, the cardiac AMP-signal receptor AMPKα2 was upregulated and redistributed to the nuclear compartment as signaling-competent phosphorylated p-AMPKα(Thr172). The cardiogenic growth factor TGF-β promoted AK1 expression, while knockdown of AK1, AK2 and AK5 activities with siRNA or suppression by hyperglycemia disrupted cardiogenesis compromising mitochondrial and myofibrillar network formation and contractile performance. Induction of creatine kinase, the alternate phosphotransfer pathway, compensated for adenylate kinase-dependent energetic deficits.Developmental deployment and upregulation of the adenylate kinase/AMPK tandem provides a nucleocytosolic energetic and metabolic signaling vector integral to execution of stem cell cardiac differentiation. Targeted redistribution of the adenylate kinase-AMPK circuit associated with cell cycle and asymmetric cell division uncovers a regulator for cardiogenesis and heart tissue regeneration.http://europepmc.org/articles/PMC3083437?pdf=render |
| spellingShingle | Petras P Dzeja Susan Chung Randolph S Faustino Atta Behfar Andre Terzic Developmental enhancement of adenylate kinase-AMPK metabolic signaling axis supports stem cell cardiac differentiation. PLoS ONE |
| title | Developmental enhancement of adenylate kinase-AMPK metabolic signaling axis supports stem cell cardiac differentiation. |
| title_full | Developmental enhancement of adenylate kinase-AMPK metabolic signaling axis supports stem cell cardiac differentiation. |
| title_fullStr | Developmental enhancement of adenylate kinase-AMPK metabolic signaling axis supports stem cell cardiac differentiation. |
| title_full_unstemmed | Developmental enhancement of adenylate kinase-AMPK metabolic signaling axis supports stem cell cardiac differentiation. |
| title_short | Developmental enhancement of adenylate kinase-AMPK metabolic signaling axis supports stem cell cardiac differentiation. |
| title_sort | developmental enhancement of adenylate kinase ampk metabolic signaling axis supports stem cell cardiac differentiation |
| url | http://europepmc.org/articles/PMC3083437?pdf=render |
| work_keys_str_mv | AT petraspdzeja developmentalenhancementofadenylatekinaseampkmetabolicsignalingaxissupportsstemcellcardiacdifferentiation AT susanchung developmentalenhancementofadenylatekinaseampkmetabolicsignalingaxissupportsstemcellcardiacdifferentiation AT randolphsfaustino developmentalenhancementofadenylatekinaseampkmetabolicsignalingaxissupportsstemcellcardiacdifferentiation AT attabehfar developmentalenhancementofadenylatekinaseampkmetabolicsignalingaxissupportsstemcellcardiacdifferentiation AT andreterzic developmentalenhancementofadenylatekinaseampkmetabolicsignalingaxissupportsstemcellcardiacdifferentiation |