Age-related skeletal muscle atrophy, also known as sarcopenia, diminishes the health and quality of life of many Veteran patients. However, the molecular mechanisms of age-related muscle atrophy are poorly understood, and a pharmacologic therapy does not exist. As a result, many elderly Veterans suffer the consequences of muscle atrophy, including weakness, falls, debilitation, and loss of independence. This places enormous burdens on elderly Veterans, their families, and society in general. Our long-term goal is to understand molecular mechanisms of age-related muscle atrophy, and then use that information to develop a therapy. In the previous grant cycle, we discovered Gadd45a and p21 as critical mediators of a novel molecular pathway to skeletal muscle atrophy. Aging, as well as other causes of muscle atrophy, strongly induce Gadd45a mRNA in skeletal muscle of humans, mice and rats. This increases the level of Gadd45a protein, which in turn increases p21 mRNA. As a result, the level of p21 protein rises and triggers many of the critical changes that occur during age-related skeletal muscle atrophy, including loss of protein and mitochondria, and ultimately, muscle fiber atrophy. Collectively, these results strongly suggest a key role for the Gadd45a/p21 pathway in age-related muscle atrophy. However, these data also elucidate several important areas for further investigation. For example, our data indicate that the sequential induction of Gadd45a and p21 plays a central role in skeletal muscle atrophy;but we do not yet know how aging increases skeletal muscle Gadd45a expression, or how Gadd45a increases p21 expression. In addition, our data suggest the Gadd45a/p21 pathway as a potential therapeutic target in age-related skeletal muscle atrophy;but this hypothesis has not yet been tested. To resolve these important issues, we propose three specific aims, all using mouse models.
In Aim 1, we will test the hypothesis that two transcription factors (p53 and ATF4) are responsible for increasing Gadd45a mRNAs during skeletal muscle aging.
In Aim 2, we will test the hypothesis that two Gadd45a-interacting proteins (MEKK4 and LRRC14) play key roles in Gadd45a-mediated p21 expression.
In Aim 3, we will test the hypothesis that reducing Gadd45a and/or p21 permits recovery of skeletal muscle mitochondria and muscle fiber size in aged, atrophic muscle. Through these studies, we hope to elucidate fundamental molecular mechanisms and new therapeutic approaches for age-related muscle atrophy, a disabling condition that affects many Veteran patients.

Public Health Relevance

Muscle wasting, also known as skeletal muscle atrophy, is a very common problem in elderly Veteran patients, and leads to other problems such as weakness, reduced activity, falls, fractures, loss of independent living, and reduced quality of life. Although age-related muscle wasting is very common and serious, its causes are poorly understood and we do not have a medicine for it. In the research that we are proposing, we will study the causes of age-related muscle wasting. These studies are a very important step towards our long-term goal of finding a therapy for muscle wasting in elderly Veteran patients.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Cellular and Molecular Medicine (CAMM)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Iowa City VA Medical Center
Iowa City
United States
Zip Code
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
Fusakio, Michael E; Willy, Jeffrey A; Wang, Yongping et al. (2016) Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver. Mol Biol Cell 27:1536-51
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

Showing the most recent 10 out of 20 publications