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.
Skeletal muscle mass makes up almost 50% of the total body weight in healthy adults and it is now recognized as an important health factor. The findings from the proposed research are expected to reveal whether or not b-catenin regulation of protein synthesis is necessary for muscle growth. If confirmed, such results will be of medicinal value by providing new targets for promoting muscle growth during periods of muscle loss associated with inactivity, cancer and aging.
|Wen, Yuan; Murach, Kevin A; Vechetti Jr, Ivan J et al. (2018) MyoVision: software for automated high-content analysis of skeletal muscle immunohistochemistry. J Appl Physiol (1985) 124:40-51|
|Murach, Kevin A; McCarthy, John J (2017) MicroRNAs, heart failure, and aging: potential interactions with skeletal muscle. Heart Fail Rev 22:209-218|
|Wen, Yuan; Alimov, Alexander P; McCarthy, John J (2016) Ribosome Biogenesis is Necessary for Skeletal Muscle Hypertrophy. Exerc Sport Sci Rev 44:110-5|
|Chaillou, Thomas; Zhang, Xiping; McCarthy, John J (2016) Expression of Muscle-Specific Ribosomal Protein L3-Like Impairs Myotube Growth. J Cell Physiol 231:1894-902|
|Kirby, Tyler J; Lee, Jonah D; England, Jonathan H et al. (2015) Blunted hypertrophic response in aged skeletal muscle is associated with decreased ribosome biogenesis. J Appl Physiol (1985) 119:321-7|
|Kirby, Tyler J; Chaillou, Thomas; McCarthy, John J (2015) The role of microRNAs in skeletal muscle health and disease. Front Biosci (Landmark Ed) 20:37-77|
|Dela Cruz, Anna Christina; Vilchez, Valery; Kim, Sooyeon et al. (2015) A prospective analysis of factors associated with decreased physical activity in patients with cirrhosis undergoing transplant evaluation. Clin Transplant 29:958-64|
|Chaillou, Thomas; Jackson, Janna R; England, Jonathan H et al. (2015) Identification of a conserved set of upregulated genes in mouse skeletal muscle hypertrophy and regrowth. J Appl Physiol (1985) 118:86-97|
|Jiang, Weihua; Zhu, Jing; Zhuang, Xun et al. (2015) Lipin1 Regulates Skeletal Muscle Differentiation through Extracellular Signal-regulated Kinase (ERK) Activation and Cyclin D Complex-regulated Cell Cycle Withdrawal. J Biol Chem 290:23646-55|
|Gedaly, Roberto; Galuppo, Roberto; Daily, Michael F et al. (2014) Targeting the Wnt/?-catenin signaling pathway in liver cancer stem cells and hepatocellular carcinoma cell lines with FH535. PLoS One 9:e99272|
Showing the most recent 10 out of 20 publications