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Cardiac mTORC1 Dysregulation Impacts Stress Adaptation and Survival in Huntington's Disease

Daniel D Child1, John H Lee2, Christine J Pascua3

  • 1The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.

Cell Reports
|April 26, 2018
PubMed

Insights

Huntington's disease (HD) causes heart problems by disrupting mTORC1 activity in the heart. Restoring this activity in mouse models improved cardiac function and survival.

Area of Science:

  • Cardiovascular Biology
  • Neurodegenerative Diseases
  • Molecular Medicine

Background:

  • Huntington's disease (HD) is a genetic neurological disorder caused by CAG-repeat expansion in the Huntingtin (HTT) gene.
  • Mutant Huntingtin (mHTT) expression affects multiple organ systems beyond the brain, with increased cardiac disease incidence and mortality observed in HD patients and models.

Purpose of the Study:

  • To investigate the role of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in cardiac dysfunction associated with Huntington's disease.
  • To determine if restoring cardiac mTORC1 activity can ameliorate HD-related cardiac pathology and mortality.

Main Methods:

  • Utilized two mouse models of Huntington's disease to assess cardiac mTORC1 signaling.
  • Administered a constitutively active Rheb protein to restore cardiac mTORC1 activity.
  • Evaluated cardiac hypertrophic adaptation to stress and overall survival rates.

Main Results:

  • Demonstrated dysregulation of the mTORC1 protein complex in the hearts of HD mouse models, linked to intrinsic mHTT expression.
  • Showed that restoring cardiac mTORC1 activity via active Rheb prevented mortality and reversed the mHTT-induced impairment of hypertrophic adaptation.
  • Identified mislocalization of endogenous Rheb as a contributing factor to chronic mTORC1 dysregulation in HD hearts.

Conclusions:

  • Cardiac mHTT expression inhibits mTORC1 activity, leading to limited heart growth and reduced compensatory capacity under stress.
  • Restoring cardiac mTORC1 function offers a potential therapeutic strategy for mitigating cardiac mortality in Huntington's disease.

Keywords:
Huntington’s diseaseRhebheartmTOR

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