Development of dilated cardiomyopathy in Bmal1-deficient mice

Mellani Lefta, Kenneth S. Campbell, Han Zhong Feng, Jian Ping Jin, Karyn A. Esser

Research output: Contribution to journalArticlepeer-review

111 Scopus citations


Circadian rhythms are approximate 24-h oscillations in physiology and behavior. Circadian rhythm disruption has been associated with increased incidence of hypertension, coronary artery disease, dyslipidemia, and other cardiovascular pathologies in both humans and animal models. Mice lacking the core circadian clock gene, brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein (Bmal1), are behaviorally arrhythmic, die prematurely, and display a wide range of organ pathologies. However, data are lacking on the role of Bmal1 on the structural and functional integrity of cardiac muscle. In the present study, we demonstrate that Bmal1 -/-mice develop dilated cardiomyopathy with age, characterized by thinning of the myocardial walls, dilation of the left ventricle, and decreased cardiac performance. Shortly after birth the Bmal1 -/-mice exhibit a transient increase in myocardial weight, followed by regression and later onset of dilation and failure. Ex vivo working heart preparations revealed systolic ventricular dysfunction at the onset of dilation and failure, preceded by downregulation of both myosin heavy chain isoform mRNAs. We observed structural disorganization at the level of the sarcomere with a shift in titin isoform composition toward the stiffer N2B isoform. However, passive tension generation in single cardiomyocytes was not increased. Collectively, these findings suggest that the loss of the circadian clock gene, Bmal1, gives rise to the development of an age-associated dilated cardiomyopathy, which is associated with shifts in titin isoform composition, altered myosin heavy chain gene expression, and disruption of sarcomere structure.

Original languageEnglish
Pages (from-to)H475-H485
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number4
StatePublished - Aug 15 2012


  • Mechanical stiffness
  • Myosin heavy chain
  • Systolic dysfunction
  • Titin isoforms

ASJC Scopus subject areas

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


Dive into the research topics of 'Development of dilated cardiomyopathy in Bmal1-deficient mice'. Together they form a unique fingerprint.

Cite this