Skeletal muscle atrophy is a poorly understood yet nearly universal consequence of severe human illness for which no therapy currently exists. We hypothesize that a central event in the pathogenesis of skeletal muscle atrophy is increased expression of ATF4, an evolutionarily ancient transcription factor that is induced by stress. This hypothesis is based on several lines of evidence derived from our preliminary studies. First, we found that ATF4 mRNA levels were increased in atrophied skeletal muscle from human subjects with spinal cord injuries. Second, we found that transfection of mouse skeletal muscle with plasmid DNA encoding mouse ATF4 induced myofiber atrophy. Conversely, transfection of an artificial microRNA targeting ATF4 or a dominant negative ATF4 construct reduced myofiber atrophy under fasting conditions. These results identify ATF4 as a novel transcriptional regulator of muscle mass that may be both necessary and sufficient for skeletal muscle atrophy. With the long-term goal of identifying new therapeutic approaches for muscle atrophy in human patients, we propose three aims. First, to determine if ATF4 is essential for muscle atrophy, we will study skeletal muscle-specific ATF4 gene knockout mice and determine if they are resistant to fasting- or denervation- induced muscle atrophy. Second, to determine the upstream mechanism of increased ATF4 expression, we will use RNA interference in wild-type mice and determine if one of the four mammalian stress-activated eIF2alpha kinases is required for ATF4 expression and muscle atrophy. Third, to determine the downstream mechanism(s) of ATF4-mediated atrophy, we will transfect skeletal myotubes with adenovirus expressing ATF4 and determine if this decreases protein synthesis and/or increases protein breakdown. We will also study skeletal muscle-specific ATF4 gene knockout mice to determine if ATF4 is required for induction of atrophy-associated proteins that inhibit protein synthesis (4E-BP1), increase protein synthesis (atrogin-1 and MuRF1), or if ATF4 activates amino acid transporter genes that are essential for muscle atrophy.
Skeletal muscle wasting is a very common medical condition for which no treatment currently exists. We hypothesize that a central cause of skeletal muscle wasting is a protein called ATF4, which acts as a switch that turns on genes for muscle wasting. By studying ATF4 and the genes it regulates, we hope to understand how muscle wasting occurs, and to identify new ways to treat patients with muscle wasting.
|Nikonorova, Inna A; Al-Baghdadi, Rana J T; Mirek, Emily T et al. (2017) Obesity challenges the hepatoprotective function of the integrated stress response to asparaginase exposure in mice. J Biol Chem 292:6786-6798|
|Adams, Christopher M; Ebert, Scott M; Dyle, Michael C (2017) Role of ATF4 in skeletal muscle atrophy. Curr Opin Clin Nutr Metab Care 20:164-168|
|Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Atherton, Philip J; Greenhaff, Paul L; Phillips, Stuart M et al. (2016) Control of skeletal muscle atrophy in response to disuse: clinical/preclinical contentions and fallacies of evidence. Am J Physiol Endocrinol Metab 311:E594-604|
|Bullard, Steven A; Seo, Seongjin; Schilling, Birgit et al. (2016) Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4. J Biol Chem 291:17496-17509|
|Masuda, Masashi; Miyazaki-Anzai, Shinobu; Keenan, Audrey L et al. (2016) Activating transcription factor-4 promotes mineralization in vascular smooth muscle cells. JCI Insight 1:e88646|
|Moro, Tatiana; Ebert, Scott M; Adams, Christopher M et al. (2016) Amino Acid Sensing in Skeletal Muscle. Trends Endocrinol Metab 27:796-806|
|Suneja, Manish; Fox, Daniel K; Fink, Brian D et al. (2015) Evidence for metabolic aberrations in asymptomatic persons with type 2 diabetes after initiation of simvastatin therapy. Transl Res 166:176-87|
|Ebert, Scott M; Dyle, Michael C; Bullard, Steven A et al. (2015) Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy. J Biol Chem 290:25497-511|
|Adams, Christopher M; Ebert, Scott M; Dyle, Michael C (2015) Use of mRNA expression signatures to discover small molecule inhibitors of skeletal muscle atrophy. Curr Opin Clin Nutr Metab Care 18:263-8|
Showing the most recent 10 out of 18 publications