Myostatin Regulates Energy Homeostasis in the Heart and Prevents Heart Failure
| Autor: | Luca Mendler, Michael Schäfers, Thilo Borchardt, Sven Hermann, Thomas Braun, Marcus Krüger, Thomas Boettger, Nadine Biesemann, Astrid Wietelmann |
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| Rok vydání: | 2014 |
| Předmět: |
Cardiac function curve
medicine.medical_specialty Physiology Myostatin Biology musculoskeletal system medicine.disease Energy homeostasis Endocrinology AMP-activated protein kinase Heart failure Internal medicine GDF11 biology.protein medicine Glycolysis Signal transduction Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation Research. 115:296-310 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.115.304185 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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