uncoordinated transcription and compromised muscle function in the lmna-null mouse model of emery-dreifuss muscular dystrophy不协调的转录和受损肌肉功能lmna-null emery-dreifuss肌肉萎缩症的小鼠模型.pdf

Uncoordinated Transcription and Compromised Muscle Function in the Lmna-Null Mouse Model of Emery- Dreifuss Muscular Dystrophy 1 1 1 2 1 1 Viola F. Gnocchi , Juergen Scharner , Zhe Huang , Ken Brady , Jaclyn S. Lee , Robert B. White , 3 1 1. 1 . Jennifer E. Morgan , Yin-Biao Sun , Juliet A. Ellis , Peter S. Zammit * 1The Randall Division of Cell and Molecular Biophysics, King’s College London, New Hunt’s House, Guy’s Campus, London, United Kingdom, 2 Centre for Ultrastructural Imaging, King’s College London, New Hunt’s House, Guy’s Campus, London, United Kingdom, 3 The Dubowitz Neuromuscular Centre, Institute of Child Health, University College, London, United Kingdom Abstract LMNA encodes both lamin A and C: major components of the nuclear lamina. Mutations in LMNA underlie a range of tissue- specific degenerative diseases, including those that affect skeletal muscle, such as autosomal-Emery-Dreifuss muscular dystrophy (A-EDMD) and limb girdle muscular dystrophy 1B. Here, we examine the morphology and transcriptional activity of myonuclei, the structure of the myotendinous junction and the muscle contraction dynamics in the lmna-null mouse model of A-EDMD. We found that there were fewer myonuclei in lmna-null mice, of which ,50% had morphological abnormalities. Assaying transcriptional activity by examining acetylated histone H3 and PABPN1 levels indicated that there was a lack of coordinated transcription between myonuclei lacking lamin A/C. Myonuclei with abnormal morphology and transcriptional activity were distributed along the length of the myofibre, but accumulated at the myotendinous junction.