The transforming growth factor-? (TGF-?) superfamily encompasses a large group of secreted signaling molecules that play critical roles in regulating the development of many different tissues during embryogenesis as well as in maintaining and modulating the functions of these tissues in adult animals. Much of our work has focused on two highly related family members, myostatin (GDF-8) and GDF-11, which we originally cloned on the basis of their homology to known family members. We showed that mice engineered to lack myostatin have dramatic increases in skeletal muscle mass throughout the body resulting from a combination of muscle fiber hyperplasia and hypertrophy, demonstrating that myostatin normally acts to limit muscle mass. We also showed that loss of myostatin has significant beneficial effects on fat and glucose metabolism, including in models of obesity and type II diabetes. In the case of GDF-11, we showed that Gdf11 knockout mice have defects in patterning of the axial skeleton and in kidney development. Others have demonstrated that GDF-11 also plays important roles in the development of the nervous system and pancreas. Much of our effort in the past has focused on understanding the developmental consequences of eliminating the functions of these molecules as well as on identifying key regulatory and signaling components. We would now like to focus our effort on better understanding their postnatal roles, with the long-term goal of exploiting their activities for clinical applications, particularly in disease states affecting key metabolic tissues like skeletal muscle and adipose tissue. Critical to this process will be a thorough understanding of the cellular targets for these signaling molecules as well as their mode of action. As a starting point, we will attempt to use genetic strategies in mice to identify the cellular targets for myostatin and the ligands that cooperate with myostatin to regulate skeletal muscle growth.
The Specific Aims of this project are: to determine the effect of blocking Smad function in myofibers in vivo and to determine the role of satellite cells in mediating the effects of myostatin in vivo. Taken together, these studies should provide key insights into how these signaling molecules control skeletal muscle growth. Based on what is known about the biological functions of myostatin and related ligands, there has been an intense focus on manipulating this pathway to increase muscle mass and strength in patients with muscle degenerative and wasting diseases, like muscular dystrophy, sarcopenia, and cachexia, which is often seen in patients with diseases like cancer, AIDS, and sepsis. Moreover, we believe that an equally important application for such agents may turn out to be to treat metabolic diseases, like obesity and type II diabetes, which have reached near epidemic proportions not only in adults but also in children and adolescents. We believe that the studies proposed here will be a crucial step to elucidating the functions of these molecules and developing strategies to exploiting their activities for therapeutic intervention.
The overall aim of this proposal is to investigate the cellular targets for myostatin, which is a signaling molecule that plays a critical role in regulating skeletal muscle growth. These studies could have important implications for the prevention and treatment of a wide range of muscle wasting diseases, like muscular dystrophy, sarcopenia, and cachexia, as well as metabolic diseases, like obesity and type II diabetes.
|Singh, Rajan; Pervin, Shehla; Lee, Se-Jin et al. (2018) Metabolic profiling of follistatin overexpression: a novel therapeutic strategy for metabolic diseases. Diabetes Metab Syndr Obes 11:65-84|
|Chung, Hyo Kyun; Ryu, Dongryeol; Kim, Koon Soon et al. (2017) Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J Cell Biol 216:149-165|
|Bondulich, Marie K; Jolinon, Nelly; Osborne, Georgina F et al. (2017) Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice. Sci Rep 7:14275|
|Goh, Brian C; Singhal, Vandana; Herrera, Angelica J et al. (2017) Activin receptor type 2A (ACVR2A) functions directly in osteoblasts as a negative regulator of bone mass. J Biol Chem 292:13809-13822|
|Khalil, Hadi; Kanisicak, Onur; Prasad, Vikram et al. (2017) Fibroblast-specific TGF-?-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest 127:3770-3783|
|Singh, Rajan; Braga, Melissa; Reddy, Srinivasa T et al. (2017) Follistatin Targets Distinct Pathways To Promote Brown Adipocyte Characteristics in Brown and White Adipose Tissues. Endocrinology 158:1217-1230|
|Eleftheriou, Nikolas M; Sjölund, Jonas; Bocci, Matteo et al. (2016) Compound genetically engineered mouse models of cancer reveal dual targeting of ALK1 and endoglin as a synergistic opportunity to impinge on angiogenic TGF-? signaling. Oncotarget 7:84314-84325|
|Muir, Alison M; Massoudi, Dawiyat; Nguyen, Ngon et al. (2016) BMP1-like proteinases are essential to the structure and wound healing of skin. Matrix Biol 56:114-131|
|Park, Benjamin V; Freeman, Zachary T; Ghasemzadeh, Ali et al. (2016) TGF?1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer. Cancer Discov 6:1366-1381|
|Lee, Yun-Sil; Huynh, Thanh V; Lee, Se-Jin (2016) Paracrine and endocrine modes of myostatin action. J Appl Physiol (1985) 120:592-8|
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