Severe myopathy in mice lacking the MEF2/SRF-dependent gene leiomodin-3
Severe myopathy in mice lacking the MEF2/SRF-dependent gene leiomodin-3
复制标题
DOI：
10.1172/jci80115
复制
发表时间：
2015-04-01
影响因子：
15.9
通讯作者：
Liu, Ning
中科院分区：
文献类型：
--
作者：
Cenik, Bercin K.;Garg, Ankit;Liu, Ning
维持骨骼肌的结构和功能需要精确的肌节蛋白化学计量比，以便正确组装收缩装置。肌节细丝成分的缺失会导致线状肌病，这是一种与肌纤维结构和收缩能力异常相关的致命性先天性肌肉疾病。此前，我们报道了小鼠海带样家族成员40(KLHL40)的缺失会导致线状肌病和Leiomodin-3(LMOD3)的不稳定。LMOD3属于促进肌动蛋白成核的原调节蛋白相关蛋白家族。在这里，我们证明了LMOD3在小鼠体内的缺失会导致线虫性肌病。在骨骼肌中，Lmod3的转录受转录因子SRF和MEF2的调控。肌钙蛋白相关转录因子(MRTF)作为SRF共激活因子，作为肌动蛋白聚合的感受器，被肌动蛋白单体隔离在细胞质中。相反，有利于肌动蛋白聚合的条件会去抑制MRTF并激活依赖于SRF的基因。我们证明了肌动蛋白核因子LMOD3与其稳定伙伴KLHL40一起提高了MRTF-SRF的活性。反过来，SRF与MEF2合作，维持LMOD3和收缩装置的其他组件的表达，从而建立起维持骨骼肌功能的调节电路。这些发现提供了对肌节组装和肌肉功能障碍与线状肌病相关的分子基础的洞察。
Maintenance of skeletal muscle structure and function requires a precise stoichiometry of sarcomeric proteins for proper assembly of the contractile apparatus. Absence of components of the sarcomeric thin filaments causes nemaline myopathy, a lethal congenital muscle disorder associated with aberrant myofiber structure and contractility. Previously, we reported that deficiency of the kelch-like family member 40 (KLHL40) in mice results in nemaline myopathy and destabilization of leiomodin-3 (LMOD3). LMOD3 belongs to a family of tropomodulin-related proteins that promote actin nucleation. Here, we show that deficiency of LMOD3 in mice causes nemaline myopathy. In skeletal muscle, transcription of Lmod3 was controlled by the transcription factors SRF and MEF2. Myocardin-related transcription factors (MRTFs), which function as SRF coactivators, serve as sensors of actin polymerization and are sequestered in the cytoplasm by actin monomers. Conversely, conditions that favor actin polymerization de-repress MRTFs and activate SRF-dependent genes. We demonstrated that the actin nucleator LMOD3, together with its stabilizing partner KLHL40, enhances MRTF-SRF activity. In turn, SRF cooperated with MEF2 to sustain the expression of LMOD3 and other components of the contractile apparatus, thereby establishing a regulatory circuit to maintain skeletal muscle function. These findings provide insight into the molecular basis of the sarcomere assembly and muscle dysfunction associated with nemaline myopathy.