Please cite this article in press as: Han HQ, et al. Myostatin/activin pathway antagonism: Molecular basis and therapeutic potential. Int J Biochem Cell Biol (2013), http://dx.doi.org/10.1016/j.biocel.2013.05.019 ARTICLE IN PRESS G Model BC-4041; No. of Pages 15 The International Journal of Biochemistry & Cell Biology xxx (2013) xxx–xxx Contents lists available at ScienceDirect The International Journal of Biochemistry & Cell Biology journal h om epage: www.elsevier.com/locate/biocel Review Myostatin/activin pathway antagonism: Molecular basis and therapeutic potential  H.Q. Han a,∗ , Xiaolan Zhou a , William E. Mitch b , Alfred L. Goldberg c a Metabolic Disorders Department, Amgen, Thousand Oaks, CA, USA b Nephrology Division, Baylor College of Medicine, Houston, TX, USA c Department of Cell Biology, Harvard Medical School, Boston, MA, USA a r t i c l e i n f o Article history: Available online xxx Keywords: Myostatin/activin-ActRIIB signaling pathway Ubiquitin–proteasome system Ubiquitin ligases Protein breakdown Muscle wasting diseases a b s t r a c t Muscle wasting is associated with a wide range of catabolic diseases. This debilitating loss of muscle mass and functional capacity reduces the quality of life and increases the risks of morbidity and mortality. Major progress has been made in understanding the biochemical mechanisms and signaling pathways regulat- ing muscle protein balance under normal conditions and the enhanced protein loss in atrophying muscles. It is now clear that activation of myostatin/activin signaling is critical in triggering the accelerated mus- cle catabolism that causes muscle loss in multiple disease states. Binding of myostatin and activin to the ActRIIB receptor complex on muscle cell membrane leads to activation of Smad2/3-mediated transcrip- tion, which in turn stimulates FoxO-dependent transcription and enhanced muscle protein breakdown via ubiquitin–proteasome system and autophagy. In addition, Smad activation inhibits muscle protein synthesis by suppressing Akt signaling. Pharmacological blockade of the myostatin/activin-ActRIIB path- way has been shown to prevent or reverse the loss of muscle mass and strength in various disease models including cancer cachexia and renal failure. Moreover, it can markedly prolong the lifespan of ani- mals with cancer-associated muscle loss. Furthermore, inhibiting myostatin/activin actions also improves insulin sensitivity, reduces excessive adiposity, attenuates systemic inflammation, and accelerates bone fracture healing in disease models. Based on these exciting advances, the potential therapeutic benefits of myostatin/activin antagonism are now being tested in multiple clinical settings. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. © 2013 Published by Elsevier Ltd. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2. Disorders associated with muscle wasting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3. Signaling pathways regulating muscle protein balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4. Myostatin/activin signaling in muscle wasting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. Myostatin biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. Activin A biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.3. Myostatin/activin signal transduction in muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.4. Regulation of protein balance by myostatin/activin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.5. Activation of myostatin/activin signaling pathway in disease states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5. Pharmacologic inhibition of myostatin/activin signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.1. Overview of preclinical findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.2. Potential therapeutic benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.2.1. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.2.2. Chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00  This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. ∗ Corresponding author at: Metabolic Disorders Department, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Tel.: +1 805 447 4770; fax: +1 805 480 1329. E-mail address: hqhan@amgen.com (H.Q. Han). 1357-2725/$ – see front matter © 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.biocel.2013.05.019