BetaCatenin Regulation of Skeletal Muscle Hypertrophy

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DESCRIPTION (provided by applicant): As the "house-building" macromolecule of the cell, ribosome biogenesis is essential for cell growth. Despite this central role in cell growth, there remains a fundamental gap in our understanding of the role of ribosome biogenesis in adult skeletal muscle hypertrophy. Studies from our laboratory have provided evidence which supports a role for increased ribosome biogenesis in skeletal muscle hypertrophy. The current proposal will begin to directly examine the importance of ribosome biogenesis to muscle hypertrophy by testing the hypothesis that -catenin is necessary for muscle hypertrophy by increasing protein synthesis through c-myc activation of ribosome biogenesis. To conditionally, manipulate -catenin or c-myc gene expression in adult skeletal muscle we generated the HSA-MerCreMer mouse. Aim 1 will determine if �-catenin expression is necessary for skeletal muscle hypertrophy using a mechanical overload model of the plantaris muscle following catenin gene inactivation. Aim 2 will determine if increased expression of �-catenin is sufficient to stimulate skeletal muscle hypertrophy. �-catenin will be over-expressed in adult skeletal muscle by using the HSA- MerCreMer strain to generate a stabilized form of �-catenin. Aim 3 will determine if c-myc expression is necessary for skeletal muscle hypertrophy following the conditional inactivation of c-myc in adult skeletal muscle using the HSA-MerCreMer strain. The effect of gene inactivation on the hypertrophic response will be assessed by measuring morphometric (muscle weight, fiber CSA), biochemical (total protein, RNA and DNA), molecular (Western blot, RT-PCR, promoter analysis, chromatin immunoprecipitation (ChIP) and electrophorectic mobility shift assay (EMSA)) and metabolic (rates of protein synthesis and degradation) variables. The results of the proposed studies are expected to have important clinical implications by identifying new molecular targets for promoting skeletal muscle protein synthesis and hypertrophy. In the long- term, the ability to manipulate ribosome biogenesis represents a promising novel strategy to attenuate or ameliorate muscle atrophy associated with aging, bed rest and cachexia.