title: Myostatin regulates energy homeostasis in the heart and prevents heart failure.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: From the Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (N.B., L.M., A.W., M.K., T. Boettger, T. Borchardt, T. Braun); Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany (N.B.); Institute of Biochemistry, Faculty of General Medicine, University of Szeged, Szeged, Hungary (L.M.); and European Institute for Molecular Imaging, University of Münster, Münster, Germany (S.H., M.S.).
authors.forename: Nadine
authors.initials: N
authors.lastname: Biesemann
authors.affiliation: From the Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (N.B., L.M., A.W., M.K., T. Boettger, T. Borchardt, T. Braun); Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany (N.B.); Institute of Biochemistry, Faculty of General Medicine, University of Szeged, Szeged, Hungary (L.M.); and European Institute for Molecular Imaging, University of Münster, Münster, Germany (S.H., M.S.).
authors.forename: Luca
authors.initials: L
authors.lastname: Mendler
authors.affiliation: From the Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (N.B., L.M., A.W., M.K., T. Boettger, T. Borchardt, T. Braun); Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany (N.B.); Institute of Biochemistry, Faculty of General Medicine, University of Szeged, Szeged, Hungary (L.M.); and European Institute for Molecular Imaging, University of Münster, Münster, Germany (S.H., M.S.).
authors.forename: Astrid
authors.initials: A
authors.lastname: Wietelmann
authors.affiliation: From the Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (N.B., L.M., A.W., M.K., T. Boettger, T. Borchardt, T. Braun); Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany (N.B.); Institute of Biochemistry, Faculty of General Medicine, University of Szeged, Szeged, Hungary (L.M.); and European Institute for Molecular Imaging, University of Münster, Münster, Germany (S.H., M.S.).
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.affiliation: From the Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (N.B., L.M., A.W., M.K., T. Boettger, T. Borchardt, T. Braun); Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany (N.B.); Institute of Biochemistry, Faculty of General Medicine, University of Szeged, Szeged, Hungary (L.M.); and European Institute for Molecular Imaging, University of Münster, Münster, Germany (S.H., M.S.).
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.affiliation: From the Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (N.B., L.M., A.W., M.K., T. Boettger, T. Borchardt, T. Braun); Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany (N.B.); Institute of Biochemistry, Faculty of General Medicine, University of Szeged, Szeged, Hungary (L.M.); and European Institute for Molecular Imaging, University of Münster, Münster, Germany (S.H., M.S.).
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: From the Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (N.B., L.M., A.W., M.K., T. Boettger, T. Borchardt, T. Braun); Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany (N.B.); Institute of Biochemistry, Faculty of General Medicine, University of Szeged, Szeged, Hungary (L.M.); and European Institute for Molecular Imaging, University of Münster, Münster, Germany (S.H., M.S.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Boettger
authors.affiliation: From the Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (N.B., L.M., A.W., M.K., T. Boettger, T. Borchardt, T. Braun); Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany (N.B.); Institute of Biochemistry, Faculty of General Medicine, University of Szeged, Szeged, Hungary (L.M.); and European Institute for Molecular Imaging, University of Münster, Münster, Germany (S.H., M.S.). Thilo.Borchardt@mpi-bn.mpg.de Thomas.Braun@mpi-bn.mpg.de.
authors.forename: Thilo
authors.initials: T
authors.lastname: Borchardt
authors.affiliation: From the Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (N.B., L.M., A.W., M.K., T. Boettger, T. Borchardt, T. Braun); Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany (N.B.); Institute of Biochemistry, Faculty of General Medicine, University of Szeged, Szeged, Hungary (L.M.); and European Institute for Molecular Imaging, University of Münster, Münster, Germany (S.H., M.S.). Thilo.Borchardt@mpi-bn.mpg.de Thomas.Braun@mpi-bn.mpg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000150:complications / Q000235:genetics*; D019070:Cell Lineage; D004734:Energy Metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control*; D006706:Homeostasis / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D055435:Myostatin / Q000172:deficiency / Q000502:physiology*; D020710:RGS Proteins / Q000502:physiology; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000502:physiology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D055372:AMP-Activated Protein Kinases; D006003:Glycogen; D020930:MAP Kinase Kinase Kinases; D055435:Myostatin; D020710:RGS Proteins; D011993:Recombinant Fusion Proteins; D000099151:MAP Kinase Kinase Kinase 7; C525912:Mstn protein, mouse; C105345:Rgs2 protein, mouse
keywords: AMP-activated protein kinases; biochemistry; cardiomegaly; heart failure; metabolism; myostatin