Notch Serves as a Molecular Brake on Myogenesis, Protein Synthesis, and Growth in Skeletal Muscle
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University of North Carolina at Charlotte
Aging can be accompanied by aggressive loss of muscle mass (sarcopenia) and is a primary prognosticator for the reduced capacity of the elderly to accomplish basic activities of daily living. Several mechanisms within skeletal muscle lead to development of sarcopenia, including a faulty myogenic response (i.e. repair) and suppressed muscle protein synthesis (MPS) following a physiological stressor (e.g. bout of exercise). Notch has been identified as a key regulatory signaling pathway over the myogenic response, however exact roles of Notch signaling remain controversial. Moreover, regulation of MPS by Notch signaling is an unexplored area. We conducted a myriad of experiments to further elucidate Notch’s regulatory role over the myogenic response as well as to determine if Notch has a regulatory role over MPS and skeletal muscle growth. Notch1 shRNA lentiviral (LV) particles (Notch1 knockdown) and an empty LV vector were injected into the left and right gastrocnemius of C57BL/6 mice, respectively (Chapter 2). Following LV administration mice, were separated in exercising (downhill running (DHR)) and non-exercising groups. Notch1 knockdown elevated myogenic regulatory factors and increased embryonic myosin heavy chain positive fibers following DHR. Moreover, Notch1 knockdown elevated MPS rate, albeit through an unknown mechanism. Follow-up experiments conducted on C2C12 cells confirmed that chemical inhibition of Notch, via Ɣ-secretase inhibitor (GSI) treatment elevated myotube hypertrophy and MPS (Chapter 3). In chapter 3, we also demonstrated that GSI-mediated increases in MPS may occur via modulation of the Phosphatase and Tensin Homolog/Protein Kinase B/Mechanistic Target of Rapamycin signaling pathway. In chapter 4, we demonstrated that GSI treatment is also sufficient to increase MPS independent of AKT and mTOR, likely via Glycogen Synthase Kinase 3β. This work collectively demonstrates that Notch serves as a molecular brake on skeletal muscle and targeting of Notch may be a useful tactic in combatting muscle wasting conditions.
MYOGENESISNOTCHPROTEIN SYNTHESISSKELETAL MUSCLE
Gordon, ScottDréau, DidierMarriott, IanBennett, Jeanette
Thesis (Ph.D.)--University of North Carolina at Charlotte, 2018.
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