Mechanical stimuli play a major role in the 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 regulation of muscle mass has been recognized for decades, the molecular mechanisms that drive this vital process are still not known. Hence, the long-term goal of our research is to defin the molecular events through which mechanical stimuli regulate muscle mass. In this project, we aim to identify the mechanisms via which mechanical stimuli activate signaling by the mammalian target of rapamycin (mTOR). Specifically, it is now known that mTOR can exert both rapamycin-sensitive and rapamycin-insensitive signaling events, and in this project we will focus on rapamycin-sensitive mTOR (RSmTOR) signaling. We are focusing on RSmTOR signaling because our previous work established that: i) mechanical stimuli can robustly activate RSmTOR signaling; ii) RSmTOR signaling is necessary for a mechanically-induced hypertrophic response; and iii) the activation of RSmTOR signaling, in and of itself, is sufficient to induce hypertrophy. Since mechanical stimuli activate RSmTOR signaling, it follows that a mechanotransduction pathway must exist for converting mechanical information into the biochemical events that activate RSmTOR signaling. Based on our preliminary data, we are proposing that the late endosomal / lysosomal system (LEL) is a central component of this pathway. The first three aims of this project will address this concept by testing the following hypotheses: 1) Raptor is necessary for the targeting of mTOR to the LEL and, in turn, the mechanical activation of RSmTOR signaling; 2) the mechanical activation of RSmTOR signaling is due, in part, to a diacylglycerol kinase ? (DGK?)-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 RSmTOR signaling. In addition to testing these hypotheses, we will also define the extent to which Raptor, DGK?/PA and TSC2/Rheb contribute to mechanically-induced changes in protein synthesis and the induction of hypertrophy. Importantly, through the use of advanced techniques, we will be able to test all of our hypotheses in-vivo (e.g., in-vivo transfection with biosensors, skeletal muscle specific inducible knockout mice, rescue experiments in knockout mice, etc.) Furthermore, in the last aim, we will use a state-of-the-art mass spectrometry technique (NeuCode) to globally map the mechanically-regulated proteome / phosphoproteome, and with our approach, we will be able to determine which events are mediated downstream versus upstream / parallel to the activation of RSmTOR signaling. Thus, we expect that the outcomes of this project will not only fill key gaps in our current knowledge, but they will also generate a new body of knowledge that will guide the fundamental direction of future studies that are aimed at fully defining how mechanical stimuli regulate skeletal muscle mass.
Skeletal muscle is crucial for movement and whole body metabolism, and consequently, the maintenance of skeletal muscle mass is essential for mobility, disease prevention and quality of life. Hence, this project is relevant to public health because the outcomes could lead to the identification of targets for therapies that are aimed at preventing the loss of skeletal muscle mass that occurs during a variety of conditions such as immobilization, bed rest, cachexia, muscular dystrophies, myopathies and aging.
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