Venetian Institute of Molecular Medicine (VIMM), via Orus 2, 35129 Padova, Italy.
Molecular Endocrinology, Institute for Diabetes and Obesity, Helmholtz Zentrum München, Business Campus Garching, Parkring 13, D-85748 Garching, Germany.
Nat Commun. 2016 Aug 3;7:12397. doi: 10.1038/ncomms12397.
The myogenic regulatory factor MRF4 is highly expressed in adult skeletal muscle but its function is unknown. Here we show that Mrf4 knockdown in adult muscle induces hypertrophy and prevents denervation-induced atrophy. This effect is accompanied by increased protein synthesis and widespread activation of muscle-specific genes, many of which are targets of MEF2 transcription factors. MEF2-dependent genes represent the top-ranking gene set enriched after Mrf4 RNAi and a MEF2 reporter is inhibited by co-transfected MRF4 and activated by Mrf4 RNAi. The Mrf4 RNAi-dependent increase in fibre size is prevented by dominant negative MEF2, while constitutively active MEF2 is able to induce myofibre hypertrophy. The nuclear localization of the MEF2 corepressor HDAC4 is impaired by Mrf4 knockdown, suggesting that MRF4 acts by stabilizing a repressor complex that controls MEF2 activity. These findings open new perspectives in the search for therapeutic targets to prevent muscle wasting, in particular sarcopenia and cachexia.
肌调节因子 MRF4 在成人骨骼肌中高度表达，但功能未知。我们发现，成年肌肉中的 Mrf4 敲低会引起肥大并防止去神经诱导的萎缩。这种作用伴随着蛋白质合成的增加和广泛的肌肉特异性基因的激活，其中许多是 MEF2 转录因子的靶标。MEF2 依赖性基因是 Mrf4 RNAi 后富集的排名最高的基因集，MEF2 报告基因被共转染的 MRF4 抑制，被 Mrf4 RNAi 激活。Mrf4 RNAi 依赖性纤维大小增加被显性负 MEF2 阻止，而组成型激活的 MEF2 能够诱导肌纤维肥大。Mrf4 敲低后 MEF2 核心抑制因子 HDAC4 的核定位受损，表明 MRF4 通过稳定一个抑制复合物来控制 MEF2 活性。这些发现为寻找治疗靶点以防止肌肉消耗，特别是肌肉减少症和恶病质，开辟了新的视角。
