Skeletal muscle atrophy represents an enormous unmet medical need in Veteran patients. Frequent causes of skeletal muscle atrophy include orthopedic injuries, bed rest, advanced age, cancer, heart failure, COPD, diabetes, stroke, renal failure, critical illness and spinal cord injuy. Effects of skeletal muscle atrophy include weakness, reduced activity, falls, fractures, debilitation, prolonged hospitalization and rehabilitation, nursing home placement, and increased mortality. Although skeletal muscle atrophy has broad clinical impact in the Veteran population, a pharmacologic therapy for muscle atrophy does not exist, and current therapeutic approaches (nutrition and physical rehabilitation) are often ineffective and/or unfeasible. Our long-term goal is to develop a pharmacologic therapy for skeletal muscle atrophy. In preliminary studies, we studied human subjects to determine mRNA expression signatures of human skeletal muscle atrophy, and then used these signatures in conjunction with a novel drug discovery method to identify two small molecules (ursolic acid and compound A) as predicted pharmacologic inhibitors of human skeletal muscle atrophy. Using mouse models, we found that ursolic acid and compound A prevent and reverse skeletal muscle atrophy, increase muscle strength, and improve exercise capacity. In addition to these effects in mice, we found that ursolic acid and compound A stimulate growth of human skeletal myotubes, an in vitro model of human skeletal muscle. Importantly, data from us and others suggest that ursolic acid and compound A have favorable safety profiles, suggesting good potential for translation to Veteran patients. Although these data identify ursolic acid and compound A as exciting potential therapeutic agents to prevent and reverse skeletal muscle atrophy in Veteran patients, some critical questions remain unanswered. For example, we do not yet understand how ursolic acid and compound A reduce muscle atrophy and improve muscle function. In addition, ursolic acid and compound A are structurally dissimilar and exhibit some differences in their physiological and biochemical effects, suggesting that the combination of ursolic acid and compound A could be more beneficial than either compound alone. To determine mechanisms of action and potential for combination therapy, we propose two aims.
In Specific Aim 1, we will use human skeletal myotubes to determine cellular mechanisms that ursolic acid and compound A utilize to increase muscle mass and improve muscle function. Since skeletal muscle mass and function are tightly linked to skeletal muscle protein, mitochondria and anabolic signaling, we will test th hypotheses that ursolic acid and compound A increase the net balance of protein synthesis to protein degradation, increase mitochondrial mass and respiration, and stimulate anabolic signaling. Collectively, these studies will provide an important mechanistic foundation for clinica studies of ursolic acid and compound A in patients with skeletal muscle atrophy.
In Specific Aim 2, we will use mouse models to determine if the combination of ursolic acid and compound A is more beneficial than either compound alone. We will test the hypotheses that the combination of ursolic acid and compound A prevents and reverses skeletal muscle atrophy, increases strength, and improves exercise capacity more than either compound alone. If the combination of ursolic acid and compound A demonstrates additional benefit in muscle atrophy, combination therapy would be carried forward to clinical studies. Through these studies, we hope to develop new therapeutic agents for skeletal muscle atrophy, and quality of life of many Veteran patients. a common and debilitating condition that diminishes the health
Skeletal muscle wasting, also known as skeletal muscle atrophy, is a very common and serious problem in Veteran patients. However, a medicine for skeletal muscle atrophy does not exist. As a result, patients and their families suffer the effects of muscle wasting, including weakness, reduced activity, falls, fractures, prolonged hospitalization and rehabilitation, and loss of independent living. In our preliminary research, we discovered two chemical compounds that prevent and treat muscle wasting in mice. We find that these compounds also improve strength and exercise in mice. In the research that we are proposing, we will study how these compounds reduce muscle wasting and improve strength and exercise. We will also test whether combining these two compounds reduces muscle wasting and improves muscle function more than either compound alone. These studies are a very important step towards our long-term goal of finding a therapy for muscle wasting in Veteran patients.
|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 14 publications