title: Uncoordinated transcription and compromised muscle function in the lmna-null mouse model of Emery- Emery-Dreyfuss muscular dystrophy.
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. Indeed, in addition to the presence of abnormal myonuclei, the structure of the myotendinous junction was perturbed, with disorganised sarcomeres and reduced interdigitation with the tendon, together with lipid and collagen deposition. Functionally, muscle contraction became severely affected within weeks of birth, with specific force generation dropping as low as ∼65% and ∼27% of control values in the extensor digitorum longus and soleus muscles respectively. These observations illustrate the importance of lamin A/C for correct myonuclear function, which likely acts synergistically with myotendinous junction disorganisation in the development of A-EDMD, and the consequential reduction in force generation and muscle wasting.
authors.affiliation: The Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London, United Kingdom.
authors.forename: Viola F
authors.initials: VF
authors.lastname: Gnocchi
authors.forename: Juergen
authors.initials: J
authors.lastname: Scharner
authors.forename: Zhe
authors.initials: Z
authors.lastname: Huang
authors.forename: Ken
authors.initials: K
authors.lastname: Brady
authors.forename: Jaclyn S
authors.initials: JS
authors.lastname: Lee
authors.forename: Robert B
authors.initials: RB
authors.lastname: White
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Morgan
authors.forename: Yin-Biao
authors.initials: YB
authors.lastname: Sun
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Ellis
authors.forename: Peter S
authors.initials: PS
authors.lastname: Zammit
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D042002:Chromatin Assembly and Disassembly / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D048788:Growth and Development / Q000235:genetics; D007365:Intercellular Junctions / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D018908:Muscle Weakness / Q000235:genetics / Q000473:pathology; D009132:Muscles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D015431:Weight Loss / Q000235:genetics
chemical_list: D034904:Lamin Type A