Myostatin regulates energy homeostasis in the heart and prevents heart failure

Nadine Biesemann, Luca Mendler, Astrid Wietelmann, Sven Hermann, Michael Schäfers, Marcus Krüger, Thomas Boettger, Thilo Borchardt, Thomas Braun

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

RATIONALE:: Myostatin is a major negative regulator of skeletal muscle mass and initiates multiple metabolic changes, including enhanced insulin sensitivity. However, the function of myostatin in the heart is barely understood, although it is upregulated in the myocardium under several pathological conditions. OBJECTIVE:: Here, we aimed to decipher the role of myostatin and myostatin-dependent signaling pathways for cardiac function and cardiac metabolism in adult mice. To avoid potential counterregulatory mechanisms occurring in constitutive and germ-line-based myostatin mutants, we generated a mouse model that allows myostatin inactivation in adult cardiomyocytes. METHODS AND RESULTS:: Cardiac MRI revealed that genetic inactivation of myostatin signaling in the adult murine heart caused cardiac hypertrophy and heart failure, partially recapitulating effects of the age-dependent decline of the myostatin paralog growth and differentiation factor 11. We found that myostatin represses AMP-activated kinase activation in the heart via transforming growth factor-β-activated kinase 1, thereby preventing a metabolic switch toward glycolysis and glycogen accumulation. Furthermore, myostatin stimulated expression of regulator of G-protein signaling 2, a GTPase-activating protein that restricts Gaq and Gas signaling and thereby protects against cardiac failure. Inhibition of AMP-activated kinase in vivo rescued cardiac hypertrophy and prevented enhanced glycolytic flow and glycogen accumulation after inactivation of myostatin in cardiomyocytes. CONCLUSIONS:: Our results uncover an important role of myostatin in the heart for maintaining cardiac energy homeostasis and preventing cardiac hypertrophy.

Original languageEnglish
Pages (from-to)296-310
Number of pages15
JournalCirculation Research
Volume115
Issue number2
DOIs
StatePublished - 7 Jul 2014
Externally publishedYes

Keywords

  • AMP-activated protein kinases
  • biochemistry
  • cardiomegaly
  • heart failure
  • metabolism
  • myostatin

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