Title: Inducible Expression of MKK3 as a Potential Therapeutic to Increase Skeletal Muscle Mass
Abstract: Mechanical stimuli play a major role in the regulation of skeletal muscle mass and the maintenance of muscle mass significantly contributes to disease prevention and quality of life. While the link between mechanical stimuli and the regulation of muscle mass has been appreciated for decades the exact mechanisms that control this process remain poorly defined. Work from our lab and others has identified the mechanistic target of rapamycin complex 1 (mTORC1) as a major regulator of this process, however, little is known about the upstream pathway(s) that control the activation of mTORC1 and/or related events that potentially contribute to the mechanical regulation of protein synthesis and growth. In an effort to identify these pathway(s) our lab performed a phosphoproteome-wide analysis of the signaling events that occur in response resistance exercise in humans, as these events would represent potential members of the upstream pathway(s) that promote the activation of mTORC1, protein synthesis, and growth. These analyses revealed that mitogen-activated protein kinase kinase 3 (MKK3) undergoes a prolonged activation following resistance exercise and this event is highly correlated with the increase in myofibrillar protein synthesis (R = 0.87). Follow-up studies revealed that the prolonged activation of MKK3b is conserved in a mouse model of resistance exercise and that the activation of MKK3b is sufficient to induce mTORC1 signaling, protein synthesis, and muscle growth. Therefore, our hypothesis is that drug-induced activation of MKK3 could increase skeletal muscle mass, if supported this could present a potential therapeutic for increasing muscle mass in conditions such as sarcopenia, disuse atrophy, and cancer cachexia. To establish the proof-of-concept for this hypothesis we generated a doxycycline-inducible, constitutively active MKK3 construct (TRE-MKK3CA). Our studies revealed that TRE-MKK3CA activates its canonical signaling pathway and increases myotube size in vitro. In vivo studies, using mice with a skeletal muscle-specific reverse tetracycline trans-activator (HSA-rtTA), also demonstrate that TRE-MKK3CA activates its canonical signaling (including the activation of signaling through mTORC1), providing further support for the notion that drug-induced activation of MKK3 can lead to skeletal muscle growth. Future experiments will investigate whether TRE-MKK3bCA is sufficient to induce muscle hypertrophy in adult mice and in models of muscle atrophy.
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