Education

Postdoctoral Fellow
University of Texas Southwestern Medical Center, 1994
Ph.D.
Texas Tech University Health Science Center, 1990

Research Information

Signaling Mechanism of Striated Muscle Remodeling

Striated muscle (skeletal and cardiac muscle) undergoes remodeling, either positive or negative, in response to physiological and pathological stress. For example, many inflammatory diseases including cancer, AIDS, sepsis, diabetes, and congestive heart failure induce debilitating muscle atrophy or wasting due to loss of muscle mass (cachexia). On the other hand, diseased or injured muscle has the capacity to regenerate leading to recovery of muscle mass and function. In addition, cardiac muscle chronically exposed to high blood pressure develops hypertrophy and eventually left ventricle dilation (congestive heart failure). The research in my lab is aimed to dissect the signaling mechanisms that regulate the remodeling processes using cellular and molecular approaches, and to test therapeutic strategies using in vitro and in vivo models. We are currently working on three research projects.

1. Mechanism of skeletal muscle wasting
Our lab and others have shown that inflammatory mediators that activate NF-κB and p38 MAPK play an important role in mediating muscle protein loss associated with many diseases. We investigate the signaling mechanisms of inflammatory mediator stimulation of the ubiquitin-proteasome pathway and the autophagy-lysosome pathway which are responsible for accelerated muscle protein degradation. We also conduct experimental therapy using animal models of muscle wasting and try to translate the basic research into clinical interventions for human patients.

2. Regulation of skeletal muscle regeneration
Skeletal muscle adapts to various stresses (injury, disease and training) by regenerating to make new muscle (myogenesis). Muscle regeneration is the function of muscle stem cells (also known as satellite cells) that have the capacity to proliferate, differentiate and fuse to form new muscle fibers when stimulated by myogenic cues. We study how these cells sense chemical or mechanical cues of myogenesis via their plasma membrane and activate specific intracellular signaling pathways that initiate muscle specific gene expression. We are particularly interested in the role of some membrane proteins including TNF-α converting enzyme (TACE) and integrins in regulating muscle gene expression.

3. Signaling mechanism of cardiac muscle adaptation to mechanical stress.
Cardiac muscle responds to chronic hemodynamic overloading (mechanical stress) by developing hypertrophy (adaptation) that leads to left ventricle dilation (maladaptation). We study the mechanotransduction mechanism that mediates cardiac muscle response to overloading with the purpose of identifying ways to prevent the maladaptation specifically without blocking adaptation. Particularly, we focus on the mechanism that mediates TACE activation by overloading.

Publications

Publication Information

  • Sin TK, Zhang G, Zhang Z, Zhu JZ, Zuo Y, Frost JA, Li M and Li Y-P. (2021). Cancer-induced muscle wasting requires p38β MAPK-mediated activation of p300. Cancer Res. 81:885–97.
  • Liu M, Zhang Y, Yang J, Cui X, Zhou Z, Zhan H, Ding K, Tian X, Yang Z, Fung K-MA, Edil BH, Postier RG, Bronze MS, Fernandez-Zapico ME, Stemmler MP, Brabletz T, Li Y-P, Houchen CW, and Li M.  (2019). ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin α3β1 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells.  Gastroenterology, Nov 8. pii: S0016-5085(19)41529-1. doi: 10.1053/j.gastro.2019.10.038.
  • Sin KWT, Zhu JZ, Zhang G, and Li Y-P. (2019).  p300 Mediates Muscle Wasting in Lewis Lung Carcinoma. Cancer Research. 79(7):1331-1342.
  • Sin TK, Zhang G, Zhang Z, Gao S, Li M and Li Y-P.  (2019).  Cancer Takes a Toll on Skeletal Muscle by Releasing Heat Shock Proteins—An Emerging Mechanism of Cancer-Induced Cachexia.  Cancers  30; 11(9):1272. doi:10.3390/cancers11091272. This is an invited article for the Special Edition “Cancer Cachexia”.
  • Yang J, Zhang Z, Zhang Y, Ni X, Zhang G, Cui X, Liu M, Xu C, Zhang Q, Zhu VF, Luo Y, Hagan JP, Li Z, Fang J, Jatoi A, Fernandez-Zapico ME, Zheng Li, Edil BH, Bronze MS, Houchen CW, Li Y-P* and Li M*. (2019).  ZIP4 Promotes Muscle Wasting and Cachexia in Mice with Orthotopic Pancreatic Tumors by Stimulating Rab27b-Regulated Cancer Cell Release of Extracellular Vesicles. Gastroenterology 156:722-734.  Epub 2018/10/21.  *Co-corresponding author
  • Liu Z, Sin KWT, Ding H, Doan HA, Gao S, Miao H, Wei Y, Wang Y, Zhang G, and Li Y-P. (2018). p38b MAPK Mediates ULK1-Dependent Induction of Autophagy in Skeletal Muscle of Tumor-Bearing Mice. Cell Stress 2(11): 311-324.
  • Liu M, Yang J, Zhang Y, Zhou Z, Cui X, Zhang L, Fung KM, Zheng W, Allard FD, Yee EU, Ding K, Wu H, Liang Z, Zheng L, Fernandez-Zapico ME, Li Y-P, Bronze MS, Morris KT,  Postier RG, Houchen CW, Yang J, Li M. (2018).  ZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and Claudin-1 through a ZEB1-Dependent Transcriptional Mechanism.  Clin Cancer Res. 24(13):3186-3196.
  • Zhang G, Liu Z, Ding H, Zhou Y, Doan H, Sin KWT, Zhu ZJ, Flores R, Wen Y, Gong X, Liu Q and Li Y-P. (2017). Tumour Induces Muscle Wasting in Mice through Releasing Extracellular Hsp70 and Hsp90. Nature Communications, 19;8(1):589. DOI: 10.1038/ s41467-017-00726-x.
  • Zhang G, Liu Z, Ding H, Miao H, Garcia JM, Li YP.  (2017).  Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways. Sci Rep. May 23;7(1):2273. doi: 10.1038/s41598-017-02347-2.
  • Ding H, Zhang G, Sin KWT, Liu Z, Lin R-K, Li M and Li Y-P. (2016). Activin A induces skeletal muscle catabolism via p38β mitogen-activated protein kinase. J Cachexia Sarcopenia Muscle, DOI: 10.1002/jcsm.12145.
  • Chen JA, Splenser A, Guillory B, Luo J, Mendiratta M, Belinova B, Halder T, Zhang G, Li Y-P, Garcia JM. (2015).  Ghrelin prevents tumour- and cisplatin-induced muscle wasting: characterization of multiple mechanisms involved. J Cachexia Sarcopenia Muscle, Jun;6(2):132-43.
  • Niu A, Wang B, and Li Y-P. (2015). TNF-α shedding in Mechanically Stressed Cardiomyocytes is mediated by Src Activation of TACE.  J Cell Biochem., 116:559-65.
  • Niu A, Wen Y, Liu H, Zhan M, Jin J, and Li Y-P. (2013). Src mediates mechanical activation of myogenesis by activating TNFα converting enzyme. J Cell Sci., 126:4349–4357. PMC3784819.
  • Zhang G, Lin R-K, Kwon Y-T, Li Y-P. (2013). Signaling mechanism of tumor cell-induced upregulation of E3 ubiquitin ligase UBR2. FASEB J., 27:2893-901.
  • Zhang G, and Li Y-P. (2012). p38beta MAPK upregulates atrogin1/MAFbx by specific phosphorylation of C/EBP-beta. Skelet Muscle. Oct 9; 2(1):20.
  • Zhang G, Jin B, and Li Y-P. (2011). C/EBPß mediates tumor-induced ubiquitin ligase atrogin1/MAFbx upregulation and muscle wasting. EMBO J, 30:4323-4335.
  • Liu H, Niu A, Chen S-E and Li Y-P. (2011). ß3-integrin mediates satellite cell differentiation in regenerating mouse muscle. FASEB J, 25:1914-21.
  • Doyle A,  Zhang G,  Abd-El-Fatah EA,  Eissa NT, and Li Y-P. (2011). Toll-like receptor 4 regulates lipopolysaccharide-induced muscle catabolism via coordinate activation of autophagy-lysosome and ubiquitin-proteasome pathways. FASEB J, 25:99-110
  • Liu H, Chen S, Jin B, Carson JA, Niu A, Durham W, Lai J-Y and Li Y-P. (2010). TIMP3: A Physiological Regulator of Adult Myogenesis. J Cell Sci  123: 2914-2921.
  • Chen S, Jin B, and Li Y-P. (2007). TNF-a Regulates myogenesis and muscle regeneration by activating p38 MAPK. Am J Physiol – Cell Physiol., 292: C1660–C1671.
  • Zhan M, Jin B, Chen S, Reecy JM, Li Y-P. (2007). TACE Release of TNF-α Mediates Mechanotransduction-Induced Activation of p38 MAPK and Myogenesis. J. Cell Sci., 15;120(Pt 4):692-701.
  • Chen S, Gerken E, Zhang Y, Mohan RK, Li AS, Reid MB, and Li Y-P. (2005). Role of TNF-a signaling in regeneration of cardiotoxin-injured muscle. Am J Physiol. – Cell Physiol., 289(5):C1179-87.