Evaluation of follistatin as a therapeutic in models of skeletal muscle atrophy associated with denervation and tenotomy.
Evaluation of follistatin as a therapeutic in models of skeletal muscle atrophy associated with denervation and tenotomy.
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DOI：
10.1038/srep17535
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发表时间：
2015-12-11
影响因子：
4.6
通讯作者：
Gregorevic P
中科院分区：
文献类型：
--
作者：
Sepulveda PV;Lamon S;Hagg A;Thomson RE;Winbanks CE;Qian H;Bruce CR;Russell AP;Gregorevic P
Follistatin是TGF-β超家族配体的抑制剂，可抑制骨骼肌生长并促进肌肉萎缩。因此，卵泡抑素已成为一种潜在的治疗方法，以改善肌肉萎缩的有害影响。然而，目前尚不清楚卵泡抑素的合成代谢作用是否在不同的非退行性肌肉萎缩模式中是保守的。在这项研究中，在去神经支配或肌腱切断前两周，将表达卵泡抑素（rAAV:Fst）的重组腺相关病毒载体传递到小鼠后肢肌肉组织，促进肌肉肥大，足以保持与未经治疗的假手术肌肉相当的肌肉质量。然而，在去神经支配或肌腱切断术时给予肌肉rAAV:Fst并不能防止随后的肌肉萎缩。rAAV:Fst给神经支配或去神经支配肌肉增加蛋白质合成，但仅在神经支配肌肉中显著降低蛋白质降解。与蛋白质合成相关的信号蛋白mTOR和S6RP的磷酸化在给予rAAV:Fst的神经支配肌肉中增加，但在去神经支配肌肉中没有增加。这些结果表明卵泡抑素的合成代谢作用受肌纤维和运动神经之间相互作用的影响。这些发现对于理解以卵泡抑素为基础的治疗非退行性肌肉萎缩的潜在疗效具有重要意义。
Follistatin is an inhibitor of TGF-β superfamily ligands that repress skeletal muscle growth and promote muscle wasting. Accordingly, follistatin has emerged as a potential therapeutic to ameliorate the deleterious effects of muscle atrophy. However, it remains unclear whether the anabolic effects of follistatin are conserved across different modes of non-degenerative muscle wasting. In this study, the delivery of a recombinant adeno-associated viral vector expressing follistatin (rAAV:Fst) to the hind-limb musculature of mice two weeks prior to denervation or tenotomy promoted muscle hypertrophy that was sufficient to preserve muscle mass comparable to that of untreated sham-operated muscles. However, administration of rAAV:Fst to muscles at the time of denervation or tenotomy did not prevent subsequent muscle wasting. Administration of rAAV:Fst to innervated or denervated muscles increased protein synthesis, but markedly reduced protein degradation only in innervated muscles. Phosphorylation of the signalling proteins mTOR and S6RP, which are associated with protein synthesis, was increased in innervated muscles administered rAAV:Fst, but not in treated denervated muscles. These results demonstrate that the anabolic effects of follistatin are influenced by the interaction between muscle fibres and motor nerves. These findings have important implications for understanding the potential efficacy of follistatin-based therapies for non-degenerative muscle wasting.