Losartan restores skeletal muscle remodeling and protects against disuse atrophy in sarcopenia.

Abstract

Sarcopenia, a critical loss of muscle mass and function because of the physiological process of aging, contributes to disability and mortality in older adults. It increases the incidence of pathologic fractures, causing prolonged periods of hospitalization and rehabilitation. The molecular mechanisms underlying sarcopenia are poorly understood, but recent evidence suggests that increased transforming growth factor-β (TGF-β) signaling contributes to impaired satellite cell function and muscle repair in aged skeletal muscle. We therefore evaluated whether antagonism of TGF-β signaling via losartan, an angiotensin II receptor antagonist commonly used to treat high blood pressure, had a beneficial impact on the muscle remodeling process of sarcopenic mice. We demonstrated that mice treated with losartan developed significantly less fibrosis and exhibited improved in vivo muscle function after cardiotoxin-induced injury. We found that losartan not only blunted the canonical TGF-β signaling cascade but also modulated the noncanonical TGF-β mitogen-activated protein kinase pathway. We next assessed whether losartan was able to combat disuse atrophy in aged mice that were subjected to hindlimb immobilization. We showed that immobilized mice treated with losartan were protected against loss of muscle mass. Unexpectedly, this protective mechanism was not mediated by TGF-β signaling but was due to an increased activation of the insulin-like growth factor 1 (IGF-1)/Akt/mammalian target of rapamycin (mTOR) pathway. Thus, blockade of the AT1 (angiotensin II type I) receptor improved muscle remodeling and protected against disuse atrophy by differentially regulating the TGF-β and IGF-1/Akt/mTOR signaling cascades, two pathways critical for skeletal muscle homeostasis. Thus, losartan, a Food and Drug Administration-approved drug, may prove to have clinical benefits to combat injury-related muscle remodeling and provide protection against disuse atrophy in humans with sarcopenia.

• Authors: Tyesha N Burks, Eva Andres-Mateos, Ruth Marx, Rebeca Mejias, Christel Van Erp, Jessica L Simmers, Jeremy D Walston, Christopher W Ward, Ronald D Cohn
• Journal: Science translational medicine (Sci Transl Med) Vol. 3 Issue 82 Pg. 82ra37 (May 11 2011) ISSN: 1946-6242 [Electronic] United States
• PMID: 21562229 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin Receptor Antagonists
• Receptor, Angiotensin, Type 1
• Transforming Growth Factor beta
• Insulin-Like Growth Factor I
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Losartan

Topics

• Angiotensin Receptor Antagonists (pharmacology, therapeutic use)
• Animals
• Insulin-Like Growth Factor I (metabolism)
• Losartan (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Muscle, Skeletal (drug effects, pathology)
• Muscular Disorders, Atrophic (complications, drug therapy, pathology, prevention & control)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, Angiotensin, Type 1 (metabolism)
• Sarcopenia (complications, drug therapy, prevention & control)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Transforming Growth Factor beta (metabolism)