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Normal cardiac function in mice with supraphysiological cardiac creatine levels.

Publication ,  Journal Article
Santacruz, L; Hernandez, A; Nienaber, J; Mishra, R; Pinilla, M; Burchette, J; Mao, L; Rockman, HA; Jacobs, DO
Published in: American journal of physiology. Heart and circulatory physiology
February 2014

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.

Duke Scholars

Published In

American journal of physiology. Heart and circulatory physiology

DOI

EISSN

1522-1539

ISSN

0363-6135

Publication Date

February 2014

Volume

306

Issue

3

Start / End Page

H373 / H381

Related Subject Headings

  • Transgenes
  • Promoter Regions, Genetic
  • Phosphocreatine
  • Myosin Heavy Chains
  • Myocardium
  • Mice, Transgenic
  • Mice
  • Membrane Transport Proteins
  • Humans
  • Heart
 

Citation

APA
Chicago
ICMJE
MLA
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Santacruz, L., Hernandez, A., Nienaber, J., Mishra, R., Pinilla, M., Burchette, J., … Jacobs, D. O. (2014). Normal cardiac function in mice with supraphysiological cardiac creatine levels. American Journal of Physiology. Heart and Circulatory Physiology, 306(3), H373–H381. https://doi.org/10.1152/ajpheart.00411.2013
Santacruz, Lucia, Alejandro Hernandez, Jeffrey Nienaber, Rajashree Mishra, Miguel Pinilla, James Burchette, Lan Mao, Howard A. Rockman, and Danny O. Jacobs. “Normal cardiac function in mice with supraphysiological cardiac creatine levels.American Journal of Physiology. Heart and Circulatory Physiology 306, no. 3 (February 2014): H373–81. https://doi.org/10.1152/ajpheart.00411.2013.
Santacruz L, Hernandez A, Nienaber J, Mishra R, Pinilla M, Burchette J, et al. Normal cardiac function in mice with supraphysiological cardiac creatine levels. American journal of physiology Heart and circulatory physiology. 2014 Feb;306(3):H373–81.
Santacruz, Lucia, et al. “Normal cardiac function in mice with supraphysiological cardiac creatine levels.American Journal of Physiology. Heart and Circulatory Physiology, vol. 306, no. 3, Feb. 2014, pp. H373–81. Epmc, doi:10.1152/ajpheart.00411.2013.
Santacruz L, Hernandez A, Nienaber J, Mishra R, Pinilla M, Burchette J, Mao L, Rockman HA, Jacobs DO. Normal cardiac function in mice with supraphysiological cardiac creatine levels. American journal of physiology Heart and circulatory physiology. 2014 Feb;306(3):H373–H381.

Published In

American journal of physiology. Heart and circulatory physiology

DOI

EISSN

1522-1539

ISSN

0363-6135

Publication Date

February 2014

Volume

306

Issue

3

Start / End Page

H373 / H381

Related Subject Headings

  • Transgenes
  • Promoter Regions, Genetic
  • Phosphocreatine
  • Myosin Heavy Chains
  • Myocardium
  • Mice, Transgenic
  • Mice
  • Membrane Transport Proteins
  • Humans
  • Heart