Cardiac muscle ring finger-1 Increases susceptibility to heart failure in Vivo

Monte Willis, Jonathan C. Schisler, Luge Li, Jessica E. Rodríguez, Eleanor G. Hilliard, Peter C. Charles, Cam Patterson

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Muscle ring finger (MuRF)1 is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates and heterodimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal, whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy, indicating cooperative control of muscle mass by MuRF1 and MuRF2. To identify the unique role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg+) hearts exhibited a nonprogressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by transaortic constriction (TAC) induced rapid failure of MuRF1 Tg+ hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg+ hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg + mice did not differ from wild-type mice despite the depressed contractility following TAC. In comparing the level and activity of creatine kinase (CK) between wild-type and MuRF1 Tg+ hearts, we found that mCK and CK-M/B protein levels were unaffected in MuRF1 Tg+ hearts; however, total CK activity was significantly inhibited. We conclude that increased expression of cardiac MuRF1 results in a broad disruption of primary metabolic functions, including alterations in CK activity that leads to increased susceptibility to heart failure following TAC. This study demonstrates for the first time a role for MuRF1 in the regulation of cardiac energetics in vivo.

Original languageEnglish (US)
Pages (from-to)80-88
Number of pages9
JournalCirculation Research
Volume105
Issue number1
DOIs
StatePublished - Jul 2 2009
Externally publishedYes

Fingerprint

Fingers
Myocardium
Heart Failure
Cardiomegaly
Creatine Kinase
Constriction
MM Form Creatine Kinase
Muscles
Proto-Oncogene Proteins c-akt
Muscle Proteins
Microarray Analysis
Cardiac Myocytes
Protein Kinase C
Hypertrophy
Transgenic Mice
Skeletal Muscle
Proteins
Adenosine Triphosphate
Genes

Keywords

  • Cardiac hypertrophy
  • Creatine kinase
  • Heart failure
  • MuRF1
  • Muscle ring finger-1
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Willis, M., Schisler, J. C., Li, L., Rodríguez, J. E., Hilliard, E. G., Charles, P. C., & Patterson, C. (2009). Cardiac muscle ring finger-1 Increases susceptibility to heart failure in Vivo. Circulation Research, 105(1), 80-88. https://doi.org/10.1161/CIRCRESAHA.109.194928

Cardiac muscle ring finger-1 Increases susceptibility to heart failure in Vivo. / Willis, Monte; Schisler, Jonathan C.; Li, Luge; Rodríguez, Jessica E.; Hilliard, Eleanor G.; Charles, Peter C.; Patterson, Cam.

In: Circulation Research, Vol. 105, No. 1, 02.07.2009, p. 80-88.

Research output: Contribution to journalArticle

Willis, M, Schisler, JC, Li, L, Rodríguez, JE, Hilliard, EG, Charles, PC & Patterson, C 2009, 'Cardiac muscle ring finger-1 Increases susceptibility to heart failure in Vivo', Circulation Research, vol. 105, no. 1, pp. 80-88. https://doi.org/10.1161/CIRCRESAHA.109.194928
Willis, Monte ; Schisler, Jonathan C. ; Li, Luge ; Rodríguez, Jessica E. ; Hilliard, Eleanor G. ; Charles, Peter C. ; Patterson, Cam. / Cardiac muscle ring finger-1 Increases susceptibility to heart failure in Vivo. In: Circulation Research. 2009 ; Vol. 105, No. 1. pp. 80-88.
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