scott-ebert@uiowa.edu
Mentor: Christopher Adams, M.D./Ph.D.
Lab Room: 540 EMRB
Lab Phone: 319-335-6746

Investigating the molecular mechanisms of skeletal muscle atrophy.

My research in Adams lab, is focused on the role of Activating Transcription Factor 4 (ATF4) in skeletal muscle atrophy. My overall hypothesis is that ATF4 plays a critical role in muscle atrophy and is based on previous work showing that atrophied skeletal muscle from rodents and humans contains elevated levels of ATF4 mRNA and that transfection of mouse skeletal muscle with plasmid encoding mouse ATF4 induces myofiber atrophy. These data suggest that ATF4 is a novel transcriptional regulator of muscle mass, whose expression increases during atrophy and promotes skeletal muscle atrophy.

Recently, I have begun to investigate the upstream signaling pathway that increases ATF4 expression in atrophied muscle, and the downstream ATF4 gene targets that might promote muscle atrophy. First, to test the hypothesis that one of the four mammalian stress-activated eIF2α kinases might increase ATF4 expression in atrophied muscle, I transfected mouse skeletal muscle with plasmid encoding eIF2αS51A, a construct that inhibits the function of all four eIF2α kinases. Interestingly, I found that eIF2α-S51A prevented the fasting-induced rise in ATF4 expression and fasting-induced myofiber atrophy. Conversely, transfection of a constitutively active eIF2α construct (S51D) increased ATF4 expression and promoted myofiber atrophy. These data suggest that fasting promotes skeletal muscle atrophy by activating one of the four eIF2α kinases, which in turn increases ATF4 expression and ATF4-dependent atrophy. Over the next 1 year, I will develop RNAi constructs to knockdown expression of each individual eIF2α kinase, and will then use these reagents to determine which eIF2α kinase drives skeletal muscle atrophy.

Publications:

Kunkel SD, Elmore CJ, Bongers KS, Ebert SM, Fox DK, Dyle MC, Bullard SA, AdamsCM. Ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance and fatty liver disease. PLoS One. 2012;7(6):e39332. Epub 2012 Jun 20. PubMed PMID: 22745735; PubMed Central PMCID: PMC3379974.

Ebert SM, Dyle MC, Kunkel SD, Bullard SA, Bongers KS, Fox DK, Dierdorff JM, Foster ED, Adams CM. Stress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy. J Biol Chem. 2012 Aug 10;287(33):27290-301. Epub 2012 Jun 12. PubMed PMID: 22692209; PubMed Central PMCID: PMC3431665.

Kunkel SD, Suneja M, Ebert SM, Bongers KS, Fox DK, Malmberg SE, Alipour F, Shields RK, Adams CM. mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Cell Metab. 2011 Jun 8;13(6):627-38. PubMed PMID: 21641545; PubMed Central PMCID: PMC3120768.

Ebert SM, Monteys AM, Fox DK, Bongers KS, Shields BE, Malmberg SE, Davidson BL, Suneja M, Adams CM. The transcription factor ATF4 promotes skeletal myofiber atrophy during fasting. Mol Endocrinol. 2010 Apr;24(4):790-9. Epub 2010 Mar 2. PubMed PMID: 20197309; PubMed Central PMCID: PMC2852358.

Abstracts:

Ebert S, Bongers K, Fox D, Adams, C. The Transcription Factor ATF4 Promotes Skeletal Myofiber Atrophy During Fasting. Experimental Biology 2011.