Position title: Associate Professor, Comparative Biosciences
Phone: School of Medicine & Public Health
- Lab Webpage:
- Hornberger Lab
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.