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 the quality of life. Although the link between mechanical stimulation and the regulation of muscle mass has been recognized for decades, the molecular mechanisms underlying this process are not known. Hence, the long-term goal of our research is to define the molecular events through which mechanical stimuli regulate skeletal muscle mass. The primary objective of this project is to define the role of the mammalian target of rapamycin (mTOR) in regulating skeletal muscle mass, and determine how mechanical stimuli activate mTOR signaling. Our rationale for focusing on mTOR comes from our preliminary studies which suggest that: i) the activation of mTOR plays a critical role in mechanically-induced growth, and ii) mechanical stimuli activate mTOR signaling through a unique PI3K/PKB- independent mechanism involving phosphatidic acid (PA). Given that mechanical stimuli activate mTOR, it follows that a molecular mechanism (i.e. mechanotransduction pathway) exists for converting mechanical signals into mTOR activation. Thus, our plan is to identify the critical events in this pathway and determine if mimicking these events can induce muscle growth and attenuate disuse atrophy. Our current hypothesis is that mechanical stimuli promote an increase in phosphatidic acid (PA) which subsequently activates mTOR signaling and ultimately growth. To test this hypothesis we will pursue the following four specific aims: 1) Determine if the activation of mTOR is sufficient to induce growth and attenuate disuse atrophy;2) Define the role of mTOR in mechanically-induced growth;3) Determine if an increase in [PA] is sufficient to induce growth and attenuate disuse atrophy and 4) Identify the upstream molecules that regulate the mechanical activation of mTOR. In the first aim, over-expression of Rheb will be used to induce a PI3K/PKB-independent activation of mTOR in mouse skeletal muscles, and the resulting effect on muscle mass during normal use and disuse will be determined. In the second aim, transgenic mice expressing various mutants of mTOR will be used to define the muscle specific role of mTOR, and mTOR kinase activity, in mechanically-induced growth. In the third aim, over-expression of PA synthesizing enzymes will be used to determine if an increase in [PA] is sufficient to induce growth and attenuate disuse atrophy. In the fourth aim, activity assays will be used to identify the enzymes that regulate mechanically-induced changes in PA, and then pharmacological and molecular interventions will be used to further define the role that these enzymes play in the mechanical activation of mTOR. The proposed studies are significant because the outcomes will fill major gaps in our current knowledge of how mechanical stimuli regulate mTOR signaling and skeletal muscle mass. Furthermore, the outcomes could lead to the identification of targets for therapies that mimic the effects of mechanical stimuli and, in-turn, prevent atrophy during periods of disuse such as bedrest, immobilization and aging.
The proposed studies have broad application to health-related research and could lead to the development of therapies aimed at preventing skeletal muscle atrophy during conditions such as bedrest, immobilization, spaceflight, aging, cachexia and dystrophy.
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