FoxO signaling and skeletal muscle atrophy

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Project Summary/Abstract Cachexia is characterized by progressive skeletal muscle and body weight loss and affects up to 80% of cancer patients. Since this loss of muscle mass contributes to weakness, reduced tolerance to conventional treatments, and increased mortality, understanding the mechanisms that drive muscle wasting is critical to the development of treatments to improve quality of life and enhance survival of cancer patients. Published and unpublished data from our lab have identified the Forkhead Box (Fox) Class O protein, FoxO1, as a critical regulator of muscle wasting that is associated with cachexia in cancer patients. We identified the transcriptional repressor, FoxP1, as a target gene upregulated by FoxO1 in response to tumor burden (TBu) that is increased at time points which precede and parallel muscle wasting and is also increased in muscle of cachectic cancer patients. In preliminary experiments we found that FoxP1 a) may act as a potent repressor of key transcription factors and genes involved in muscle contraction and the maintenance of muscle integrity, b) is sufficient to induce muscle fiber atrophy and c) is required for muscle fiber atrophy induced by TBu, thus implicating FoxP1 in the cachectic phenotype. Aims 1 and 2 will therefore test our underlying hypothesis that FoxP1 is sufficient to induce deterioration of muscle ultrastructure, activation of catabolic pathways, and muscle atrophy and weakness and that its upregulation in response to TBu is required for these tumor-induced muscle pathologies. Specific Aim 1: We will establish the role and investigate the molecular mechanisms by which FoxP1 is sufficient to induce muscle wasting. Specific Aim 2: To establish the role and investigate the mechanisms by which a FoxO1-FoxP1-MEF2c axis drives cancer-induced muscle wasting. We will test these hypotheses in a conventional pre-clinical mouse model of cachexia as well as in a novel mouse model of cancer cachexia in which primary resected tumors from pancreatic ductal adenocarcinoma (PDAC) patients are attached to the pancreas of immunocompromised mice to create mouse avatars. Specific Aim 3: To identify changes in the skeletal muscle transcriptome and proteome of weight losing PDAC patients and their mouse avatars during the progression of cancer cachexia. Our third aim takes advantage of our wide access to muscle and tumor tissue from PDAC patients. We thus propose an unbiased approach to identify the transcriptome (via RNA-seq) and proteome (via iTRAQ) in muscle of PDAC patients as well as their mouse avatars during the progression of cachexia as a surrogate for longitudinal studies in humans. We propose to complement these findings with muscle histology and ultrastructure. We anticipate that our findings from Aims 1 and 2 will elucidate key mechanisms of wasting and weakness in response to TBu, while data generated in Aim 3 will generate a plethora of new knowledge to guide future pre- clinical and clinical studies aimed at preventing or retarding cancer-induced cachexia in the human condition.