Graduate Thesis Or Dissertation
 

Homeodomain Transcription Factor Pitx2 is Required for Muscle Maintenance and Energy Homeostasis

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/4m90f200z

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  • Skeletal muscle, the largest organ in the body in mass, is composed by 600 specialized muscles in humans with unique biochemical, physiological and metabolic identities. Skeletal muscles control body movement, locomotion, and nutrient balance. Muscle formation requires precisely orchestrated environmental signals and regulatory gene networks in time and space. Gene perturbations result in myopathies and systemic metabolic diseases. Pitx2, a homeobox gene, is expressed in muscle anlagen, specifies craniofacial and abdominal muscles and regulates skeletal muscle higher order assembly. Null Pitx2 mutant mice die at embryonic day 10-14 due to multiple organ arrest. To investigate the cellular and molecular functions of Pitx2 in skeletal muscles, we generated a mouse model in which, Pitx2 was selectively disrupted in fetal/neonatal myofibers under the influence of the muscle creatine kinase (Mck) driver (Pitx2MCK). Muscle function and energy production were defective in Pitx2MCK mice. Oxidative fibers were distorted, the Foxo3-dependent mitophagy pathway was activated and the contractile apparatus was compromised followed by glucose and lipid exhaustion. The catabolic state of the skeletal muscle resulted in systemic metabolic dysfunction, insulin sensitivity, cirrhotic liver, bone loss, increased white adipocytes and morbid obesity, all characteristics of the Metabolic Syndrome. Our findings establish Pitx2 as a novel player of muscle integrity and energy homeostasis.
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  • Ongoing Research
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  • 2018-06-08 to 2020-07-09

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