Normal cardiac function in mice with supraphysiological cardiac creatine levels

Lucia Santacruz, Alejandro Hernandez, Jeffrey Nienaber, Rajashree Mishra, Miguel Pinilla, James Burchette, Lan Mao, Howard A. Rockman, Danny O. Jacobs

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Creatine and phosphocreatine levels are decreased in heart failure, and reductions in myocellular phosphocreatine levels predict the severity of the disease and portend adverse outcomes. Previous studies of transgenic mouse models with increased creatine content higher than two times baseline showed the development of heart failure and shortened lifespan. Given phosphocreatine's role in buffering ATP content, we tested the hypothesis whether elevated cardiac creatine content would alter cardiac function under normal physiological conditions. Here, we report the creation of transgenic mice that overexpress the human creatine transporter (CrT) in cardiac muscle under the control of the α-myosin heavy chain promoter. Cardiac transgene expression was quantified by qRT-PCR, and human CrT protein expression was documented on Western blots and immunohistochemistry using a specific anti-CrT antibody. High-energy phosphate metabolites and cardiac function were measured in transgenic animals and compared with age-matched, wild-type controls. Adult transgenic animals showed increases of 5.7- and 4.7-fold in the content of creatine and free ADP, respectively. Phosphocreatine and ATP levels were two times as high in young transgenic animals but declined to control levels by the time the animals reached 8 wk of age. Transgenic mice appeared to be healthy and had normal life spans. Cardiac morphometry, conscious echocardiography, and pressure-volume loop studies demonstrated mild hypertrophy but normal function. Based on our characterization of the human CrT protein expression, creatine and phosphocreatine content, and cardiac morphometry and function, these transgenic mice provide an in vivo model for examining the therapeutic value of elevated creatine content for cardiac pathologies.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume306
Issue number3
DOIs
StatePublished - Feb 1 2014
Externally publishedYes

Fingerprint

Creatine
Phosphocreatine
Transgenic Mice
Genetically Modified Animals
Heart Failure
Adenosine Triphosphate
Myosin Heavy Chains
Transgenes
Adenosine Diphosphate
Hypertrophy
Echocardiography
Myocardium
Proteins
Western Blotting
Immunohistochemistry
Phosphates
Pathology
Pressure
Polymerase Chain Reaction
creatine transporter

Keywords

  • Cardiac failure
  • Creatine transporter
  • Energy metabolism
  • Phosphocreatins

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Normal cardiac function in mice with supraphysiological cardiac creatine levels. / Santacruz, Lucia; Hernandez, Alejandro; Nienaber, Jeffrey; Mishra, Rajashree; Pinilla, Miguel; Burchette, James; Mao, Lan; Rockman, Howard A.; Jacobs, Danny O.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 306, No. 3, 01.02.2014.

Research output: Contribution to journalArticle

Santacruz, L, Hernandez, A, Nienaber, J, Mishra, R, Pinilla, M, Burchette, J, Mao, L, Rockman, HA & Jacobs, DO 2014, 'Normal cardiac function in mice with supraphysiological cardiac creatine levels', American Journal of Physiology - Heart and Circulatory Physiology, vol. 306, no. 3. https://doi.org/10.1152/ajpheart.00411.2013
Santacruz, Lucia ; Hernandez, Alejandro ; Nienaber, Jeffrey ; Mishra, Rajashree ; Pinilla, Miguel ; Burchette, James ; Mao, Lan ; Rockman, Howard A. ; Jacobs, Danny O. / Normal cardiac function in mice with supraphysiological cardiac creatine levels. In: American Journal of Physiology - Heart and Circulatory Physiology. 2014 ; Vol. 306, No. 3.
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