Lamin A N-terminal phosphorylation is associated with myoblast activation: impairment in Emery-Dreifuss muscular dystrophy
Lamin A N-terminal phosphorylation is associated with myoblast activation: impairment in Emery-Dreifuss muscular dystrophy
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DOI：
10.1136/jmg.2004.026112
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发表时间：
2005-03-01
影响因子：
4
通讯作者：
Lattanzi, G
中科院分区：
文献类型：
--
作者：
Cenni, V;Sabatelli, P;Lattanzi, G
背景资料：与核纤层蛋白A/C基因突变相关的骨骼肌疾病包括常染色体Emery-Dreifuss型肌营养不良症和肢带型肌营养不良症1B。这些疾病的致病机制尚不清楚。最近的数据表明，信号传导机制的损害可能是肌肉功能障碍的原因。肌细胞中由核纤层蛋白A/C、埃默蛋白和核肌动蛋白形成的分子复合物已被鉴定。这种蛋白质复合物的稳定性似乎与磷酸化mechanism.Objective：分析对照组和laminopathic muscle cells.Methods：用特异性抗体测定培养的小鼠成肌细胞核纤层蛋白A/C N-末端磷酸化。对血清饥饿的成肌细胞培养物进行胰岛素处理以评估胰岛素信号传导在磷酸化途径中的参与。筛选4例Emery-Dreifuss型和1例肢带型肌营养不良症1B型患者，检测培养成肌细胞和成熟肌纤维中核纤层蛋白A/C的磷酸化水平。结果：在成肌细胞分化或增殖过程中，核纤层蛋白A磷酸化水平明显升高，静止期核纤层蛋白A/C磷酸化水平沿着降低。核纤层蛋白A的N-末端磷酸化诱导的胰岛素刺激，这反过来并不影响核纤层蛋白C的磷酸化。核纤层蛋白A/C在成熟肌肉中也过度磷酸化，主要是在再生纤维中。核纤层蛋白A/C磷酸化显着减少在laminopathic成肌细胞和肌纤维，而它是保存在间质fibroblast.Conclusions：改变核纤层蛋白A/C与肌肉特异性磷酸化合作伙伴的相互作用可能参与Emery-Dreifuss型肌营养不良症和肢带型肌营养不良症1B的发病机制。
Background: Skeletal muscle disorders associated with mutations of lamin A/C gene include autosomal Emery-Dreifuss muscular dystrophy and limb girdle muscular dystrophy 1B. The pathogenic mechanism underlying these diseases is unknown. Recent data suggest an impairment of signalling mechanisms as a possible cause of muscle malfunction. A molecular complex in muscle cells formed by lamin A/C, emerin, and nuclear actin has been identified. The stability of this protein complex appears to be related to phosphorylation mechanisms.Objective: To analyse lamin A/C phosphorylation in control and laminopathic muscle cells.Methods: Lamin A/C N-terminal phosphorylation was determined in cultured mouse myoblasts using a specific antibody. Insulin treatment of serum starved myoblast cultures was carried out to evaluate involvement of insulin signalling in the phosphorylation pathway. Screening of four Emery-Dreifuss and one limb girdle muscular dystrophy 1B cases was undertaken to investigate lamin A/C phosphorylation in both cultured myoblasts and mature muscle fibres.Results: Phosphorylation of lamin A was observed during myoblast differentiation or proliferation, along with reduced lamin A/C phosphorylation in quiescent myoblasts. Lamin A N-terminus phosphorylation was induced by an insulin stimulus, which conversely did not affect lamin C phosphorylation. Lamin A/C was also hyperphosphorylated in mature muscle, mostly in regenerating fibres. Lamin A/C phosphorylation was strikingly reduced in laminopathic myoblasts and muscle fibres, while it was preserved in interstitial fibroblasts.Conclusions: Altered lamin A/C interplay with a muscle specific phosphorylation partner might be involved in the pathogenic mechanism of Emery-Dreifuss muscular dystrophy and limb girdle muscular dystrophy 1B.