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Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation

Jason C Choi1, Antoine Muchir, Wei Wu

  • 1Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

Science Translational Medicine
|July 28, 2012
PubMed

Insights

Mutations in the lamin A/C gene cause dilated cardiomyopathy by disrupting cell signaling. Treating mice with a rapamycin analog improved heart function and enhanced autophagy, suggesting a new therapeutic approach for laminopathies.

Area of Science:

  • Cardiovascular Biology
  • Molecular Genetics
  • Cellular Signaling

Background:

  • Mutations in the lamin A/C gene (LMNA) lead to laminopathies, including dilated cardiomyopathy.
  • The precise molecular mechanisms by which LMNA mutations cause cardiac dysfunction remain unclear.

Purpose of the Study:

  • To investigate the role of the AKT-mammalian target of rapamycin (mTOR) pathway and autophagy in LMNA-associated cardiomyopathy.
  • To evaluate the therapeutic potential of targeting this pathway in a mouse model of LMNA cardiomyopathy.

Main Methods:

  • Analysis of AKT-mTOR pathway activation and autophagy in hearts of mice with Lmna mutation.
  • In vivo administration of temsirolimus, a rapamycin analog, to assess its effects on cardiac function.
  • Correlation of cardiac function improvement with autophagy levels.

Main Results:

  • Hyperactivation of the AKT-mTOR pathway was observed in the hearts of Lmna-mutant mice.
  • Temsirolimus treatment prevented cardiac function deterioration in these mice.
  • Defective autophagy was identified in the hearts, and its enhancement correlated with improved cardiac function.

Conclusions:

  • The AKT-mTOR pathway is implicated in the pathogenesis of LMNA cardiomyopathy.
  • Pharmacological enhancement of autophagy via rapalogs represents a promising therapeutic strategy for LMNA-related heart disease.

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