Hammers David W, Merscham-Banda Melissa, Hsiao Jennifer Ying, Engst Stefan, Hartman James J, Sweeney H Lee
Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL, USA.
Myology Institute, University of Florida College of Medicine, Gainesville, FL, USA.
EMBO Mol Med. 2017 Apr;9(4):531-544. doi: 10.15252/emmm.201607231.
Growth and differentiation factor (GDF) 11 is a member of the transforming growth factor β superfamily recently identified as a potential therapeutic for age-related cardiac and skeletal muscle decrements, despite high homology to myostatin (Mstn), a potent negative regulator of muscle mass. Though several reports have refuted these data, the effects of GDF11 on skeletal muscle mass have not been addressed. Using myoblast culture assays, we first demonstrate that GDF11 and Mstn have similar activities/potencies on activating p-SMAD2/3 and induce comparable levels of differentiated myotube atrophy. We further demonstrate that adeno-associated virus-mediated systemic overexpression of GDF11 in C57BL/6 mice results in substantial atrophy of skeletal and cardiac muscle, inducing a cachexic phenotype not seen in mice expressing similar levels of Mstn. Greater cardiac expression of may explain this GDF11-specific cardiac phenotype. These data indicate that bioactive GDF11 at supraphysiological levels cause wasting of both skeletal and cardiac muscle. Rather than a therapeutic agent, GDF11 should be viewed as a potential deleterious biomarker in muscle wasting diseases.
生长分化因子（GDF）11是转化生长因子β超家族的成员，尽管与肌肉生长抑制素（Mstn，一种肌肉质量的强效负调节因子）具有高度同源性，但最近被确定为与年龄相关的心脏和骨骼肌衰退的潜在治疗方法。尽管有几份报告反驳了这些数据，但GDF11对骨骼肌质量的影响尚未得到探讨。通过成肌细胞培养试验，我们首先证明GDF11和Mstn在激活p-SMAD2/3方面具有相似的活性/效力，并诱导相当水平的分化肌管萎缩。我们进一步证明，腺相关病毒介导的GDF11在C57BL/6小鼠中的全身过表达导致骨骼肌和心肌的实质性萎缩，诱导出在表达相似水平Mstn的小鼠中未见的恶病质表型。更高的心脏表达可能解释了这种GDF11特异性的心脏表型。这些数据表明，超生理水平的生物活性GDF11会导致骨骼肌和心肌的消瘦。GDF11不应被视为一种治疗剂，而应被视为肌肉萎缩疾病中的一种潜在有害生物标志物。
