Titles and Education
- Assc. in Chemistry, Lake Superior State University, 1996
- B.S. in Biology, Lake Superior State University, 1996
- M.A. in Kinesiology, University of Texas at Austin, 1999
- Ph.D. in Kinesiology, University of Illinois-Chicago, 2004
It is known that mechanical stimuli play a major role in regulation of skeletal muscle mass, and the maintenance of muscle mass contributes significantly to disease prevention and quality of life. Although the link between mechanical signals and the control of muscle mass has been recognized for decades, the mechanisms involved in converting mechanical information into the molecular events that control this process remain ill defined. Thus, the primary focus of our research is to determine how skeletal muscles sense mechanical information and convert this stimulus into the molecular events that regulate changes in mass (mechanotransduction).
Our studies in the field of mechanotransduction and the regulation of skeletal muscle mass have led us to focus on a protein kinase called the mammalian target of rapamycin (mTOR). We are interested in mTOR because our previous work has established that: i) mechanical stimuli can robustly activate mTOR signaling; ii) mTOR signaling is necessary for a mechanically-induced increase in muscle fiber size (hypertrophy); and iii) the activation of mTOR signaling, in and of itself, is sufficient to induce hypertrophy. Since mechanical stimuli activate mTOR signaling, it follows that a mechanotransduction pathway must exist for converting mechanical information into the biochemical events that activate mTOR. Based on our recent work, it appears that the late endosomal / lysosomal system (LEL) may be a central component of this pathway. Therefore, to test this concept, we are currently pursuing the following hypotheses: 1) Raptor is necessary for the targeting of mTOR to the LEL and, in turn, the mechanical activation of mTOR signaling; 2) the mechanical activation of mTOR signaling is due, in part, to a diacylglycerol kinase ζ (DGKζ)-dependent increase in phosphatidic acid (PA) at the LEL; and 3) mechanical stimuli induce an increase in the phosphorylation of tuberin (TSC2), which causes it to dissociate from the LEL, and as a result, Rheb at the LEL becomes activated and stimulates mTOR signaling. In addition to testing these hypotheses, we are also in the process of defining the extent to which Raptor, DGKζ/PA and TSC2/Rheb contribute to mechanically-induced changes in protein synthesis and the induction of hypertrophy.
The work in our lab involves the use of a wide variety of molecular, cellular and animal based techniques (e.g. cloning, mutagenesis, Western blotting, microscopy, metabolic tracers, in-vivo transfections, tissue specific inducible knockout transgenic mice and several models of mechanical loading). Furthermore, our lab is in the early stages of using a state-of-the-art mass spectrometry technique (NeuCode) to globally map the mechanically-regulated proteome / phosphoproteome. This is a new and particularly exciting direction that will enable us to dramatically expand our knowledge of the events that are mediated downstream versus upstream / parallel to the mechanical activation of mTOR signaling.
In summary, the long-term goal of our research is to identify targets for therapies that are aimed at mimicking the effects of mechanical stimuli and, in turn, prevent the loss of muscle mass that occurs during conditions such as immobilization, bed rest, cachexia, muscular dystrophies and aging. Moreover, it is known that mTOR signaling contributes to several diseases such as diabetes, aging and cancer, and thus, our research is also expected to benefit the ongoing efforts that are aimed at treating these diseases.
To learn more about these projects, please visit the lab website: http://www.vetmed.wisc.edu/lab/hornberger/
- Metabolic and Molecular Basis of Medicine (MMBM)
Factors that impact skeletal muscle mass
Compensatory growth of the lung
- Comparative Biomedical Sciences Graduate Program
- Program in Cellular and Molecular Biology
- Molecular and Cellular Pharmacology Training Program
- Kinesiology Graduate Program
- You, JS, Dooley MS, Kim CR, Kim EJ, Xu W, Goodman CA, and Hornberger TA, A DGKzeta-FoxO-ubiquitin proteolytic axis controls fiber size during skeletal muscle remodeling. Sci Signal, 2018 May 15; 11(530). pii: eaao6847. * Recommended by the Faculty of 1000. http://stke.sciencemag.org/content/11/530/eaao6847.long
- Wilson GM, Blanco R, Coon JJ and Hornberger TA. Identifying Novel Signaling Pathways: An Exercise Physiologist Guide to Phosphoproteomics.* Highlighted by the Editor-in-Chief and selected as the ‘Journal Club’ article in the quarterly issue. Exerc Sport Sci Rev. 2018 Apr;46(2):76-85. PMID - 29346157 (https://journals.lww.com/acsm-essr/fulltext/2018/04000/Identifying_Novel_Signaling_Pathways___An_Exercise.3.aspx)
- Jacobs BL, McNally RM, Kim KJ, Blanco R, Privett RE, You JS, and Hornberger TA. Identification of Novel Phosphorylation Sites on Tuberin (TSC2) that Regulate the Activation of Signaling by the Mammalian Target of Rapamycin (mTOR). J. Biol. Chem. 2017 Apr 28;292(17):6987-6997. * Recommended by the Faculty of 1000. http://www.jbc.org/content/292/17/6987.long
- Potts GK, McNally RM, Blanco R, You JS, Hebert AS, Westphall MS, Coon JJ, and Hornberger TA. A Map of the Phosphoproteomic Alterations that occur after a bout of Maximal Intensity Contractions. J. Physiol. 2017 Aug 1;595(15):5209-5226. * Selected for two different commentary articles. https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP273904 .
- You JS, Anderson GB, Dooley MS, and Hornberger TA. The Role of mTOR Signaling in the Regulation of Protein Synthesis and Muscle Mass During Immobilization. Dis. Model. Mech. 2015 Sep 1;8(9):1059-69. http://dmm.biologists.org/content/8/9/1059.long