McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Sci Transl Med. 2011 May 11;3(82):82ra37. doi: 10.1126/scitranslmed.3002227.
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.
肌肉减少症是一种由于生理衰老过程导致的肌肉质量和功能的严重丧失，它会导致老年人残疾和死亡。它会增加病理性骨折的发病率，导致住院和康复时间延长。肌肉减少症的分子机制尚不清楚，但最近的证据表明，转化生长因子-β（TGF-β）信号的增加导致衰老骨骼肌卫星细胞功能受损和肌肉修复受损。因此，我们评估了通过血管紧张素 II 受体拮抗剂氯沙坦（一种常用于治疗高血压的药物）拮抗 TGF-β信号是否对肌肉减少症小鼠的肌肉重塑过程有有益影响。我们证明，用氯沙坦治疗的小鼠纤维化明显减少，并且在心脏毒素诱导损伤后体内肌肉功能得到改善。我们发现，氯沙坦不仅减弱了经典的 TGF-β信号级联反应，还调节了非经典的 TGF-β丝裂原激活蛋白激酶途径。我们接下来评估了氯沙坦是否能够对抗因后肢固定而导致的衰老小鼠的废用性萎缩。我们表明，用氯沙坦治疗的固定小鼠可防止肌肉质量的丧失。出乎意料的是，这种保护机制不是由 TGF-β信号介导的，而是由于胰岛素样生长因子 1（IGF-1）/Akt/雷帕霉素靶蛋白（mTOR）通路的激活增加所致。因此，阻断 AT1（血管紧张素 II 型 1）受体通过差异调节 TGF-β和 IGF-1/Akt/mTOR 信号通路改善肌肉重塑并防止废用性萎缩，这两种途径对于骨骼肌稳态至关重要。因此，氯沙坦是一种获得美国食品和药物管理局批准的药物，可能具有临床益处，可用于对抗与损伤相关的肌肉重塑，并为肌肉减少症患者提供防止废用性萎缩的保护。
