Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved.
ATP is required for normal cardiac contractile function, and it has long been hypothesized that reduced energy delivery contributes to the contractile dysfunction of heart failure (HF). Despite experimental and clinical HF data showing reduced metabolism through cardiac creatine kinase (CK), the major myocardial energy reserve and temporal ATP buffer, a causal relationship between reduced ATP-CK metabolism and contractile dysfunction in HF has never been demonstrated. Here, we generated mice conditionally overexpressing the myofibrillar isoform of CK (CK-M) to test the hypothesis that augmenting impaired CK-related energy metabolism improves contractile function in HF. CK-M overexpression significantly increased ATP flux through CK ex vivo and in vivo but did not alter contractile function in normal mice. It also led to significantly increased contractile function at baseline and during adrenergic stimulation and increased survival after thoracic aortic constriction (TAC) surgery-induced HF. Withdrawal of CK-M overexpression after TAC resulted in a significant decline in contractile function as compared with animals in which CK-M overexpression was maintained. These observations provide direct evidence that the failing heart is "energy starved" as it relates to CK. In addition, these data identify CK as a promising therapeutic target for preventing and treating HF and possibly diseases involving energy-dependent dysfunction in other organs with temporally varying energy demands.
Department of Medicine, Cardiology Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Ashish
A
Gupta
Ashwin
A
Akki
Yibin
Y
Wang
Michelle K
MK
Leppo
V P
VP
Chacko
D Brian
DB
Foster
Viviane
V
Caceres
Sa
S
Shi
Jonathan A
JA
Kirk
Jason
J
Su
Shenghan
S
Lai
Nazareno
N
Paolocci
Charles
C
Steenbergen
Gary
G
Gerstenblith
Robert G
RG
Weiss
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D052283:Creatine Kinase, MM Form / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004280:Dobutamine / Q000494:pharmacology; D004734:Energy Metabolism; D015870:Gene Expression; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D010477:Perfusion; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D011994:Recombinant Proteins; D004280:Dobutamine; D000255:Adenosine Triphosphate; D052283:Creatine Kinase, MM Form