Summary
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.
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.
Skeletal muscle atrophy is characteristic of starvation and a common consequence of aging. It also complicates a wide range of severe human illnesses, including diabetes, cancer, chronic renal failure, congestive heart failure, chronic respiratory disease, acute critical illness, chronic infections such as HIV/AIDS, spinal cord injury (SCI), muscle denervation, and many other medical and surgical conditions that limit muscle use. However, we currently lack medical therapies to prevent or reverse skeletal muscle atrophy in humans. Sequelae of muscle atrophy (including weakness, falls, fractures, opportunistic respiratory infections, and loss of independence) are thus commonplace in hospital wards and extended care facilities.
Previous studies demonstrated that skeletal muscle atrophy is driven by conserved changes in skeletal muscle gene expression (Bodine et al., 2001a,Sandri et al., 2004). We therefore hypothesized that pharmacologic compounds with opposite effects on gene expression might inhibit skeletal muscle atrophy. To test this, we first determined an mRNA expression signature of one atrophy-inducing stress (fasting) in human and mouse skeletal muscle. We then used these unbiased data in conjunction with the Connectivity Map (Lamb et al., 2006) to identify candidate small molecule inhibitors of muscle atrophy. This approach identified a natural compound that may have applications in the treatment of human skeletal muscle atrophy.
Authors
Steven D. Kunkel
Manish Suneja
Scott M. Ebert
Kale S. Bongers
Daniel K. Fox
Sharon E. Malmberg
Fariborz Alipour
Richard K. Shields
Christopher M. Adams
Steven D. Kunkel
Manish Suneja
Scott M. Ebert
Kale S. Bongers
Daniel K. Fox
Sharon E. Malmberg
Fariborz Alipour
Richard K. Shields
Christopher M. Adams
From: http://www.cell.com/cell-metabolism/abstract/S1550-4131(11)00177-X#Summary
http://www.cell.com/cell-metabolism/abstract/S1550-4131(11)00177-X#Results
