Cell Metabolism, Volume 13, Issue 6, 627-638, 8 June 2011
Copyright © 2011 Elsevier Inc. All rights reserved.
Steven D. Kunkel, Manish Suneja, Scott M. Ebert, Kale S. Bongers, Daniel K. Fox, Sharon E. Malmberg, Fariborz Alipour, Richard K. Shields, Christopher M. AdamsSee Affiliations
We determined mRNA expression signatures of skeletal muscle atrophy in humans
Muscle atrophy signatures negatively correlated with the signature of ursolic acid
Ursolic acid reduced muscle atrophy and induced muscle hypertrophy in mice
Although ursolic acid increased skeletal muscle mass, it reduced adiposity
Skeletal muscle atrophy is a common and debilitating condition that lacks a pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs that were regulated by fasting in both human and mouse muscle, and 29 mRNAs that were regulated by both fasting and spinal cord injury in human muscle. We used these two unbiased mRNA expression signatures of muscle atrophy to query the Connectivity Map, which singled out ursolic acid as a compound whose signature was opposite to those of atrophy-inducing stresses. A natural compound enriched in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling and inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly, ursolic acid's effects on muscle were accompanied by reductions in adiposity, fasting blood glucose, and plasma cholesterol and triglycerides. These findings identify a potential therapy for muscle atrophy and perhaps other metabolic diseases.