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.).
Circ Res. 2014 Jul 7;115(2):296-310. doi: 10.1161/CIRCRESAHA.115.304185. Epub 2014 May 7.
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.
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.
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.
Our results uncover an important role of myostatin in the heart for maintaining cardiac energy homeostasis and preventing cardiac hypertrophy.
肌肉生长抑制素是骨骼肌质量的主要负调控因子，它会引发多种代谢变化，包括增强胰岛素敏感性。然而，肌肉生长抑制素在心脏中的功能尚未被充分了解，尽管它在几种病理条件下会在心肌中上调。
本研究旨在解析肌肉生长抑制素及其依赖的信号通路在成年小鼠心脏功能和心脏代谢中的作用。为避免在组成型和种系基础的肌肉生长抑制素突变体中出现潜在的代偿机制，我们构建了一种允许成年心肌细胞中肌肉生长抑制素失活的小鼠模型。
心脏 MRI 显示，成年鼠心脏中肌肉生长抑制素信号的遗传失活导致心脏肥大和心力衰竭，部分再现了肌肉生长抑制素同源物生长分化因子 11 随年龄增长而下降的效应。我们发现肌肉生长抑制素通过转化生长因子-β激活激酶 1 抑制心脏中 AMP 激活的蛋白激酶的激活，从而防止代谢向糖酵解和糖原积累转变。此外，肌肉生长抑制素刺激 G 蛋白信号调节因子 2 的表达，G 蛋白信号调节因子 2 是一种 GTP 酶激活蛋白，可限制 Gaq 和 Gas 信号，从而防止心力衰竭。体内 AMP 激活的蛋白激酶抑制可挽救心脏肥大，并防止在心肌细胞中肌肉生长抑制素失活后增强的糖酵解流和糖原积累。
我们的研究结果揭示了肌肉生长抑制素在心脏中维持心脏能量稳态和防止心脏肥大的重要作用。
