ORIGINAL ARTICLE

Lamin A N-terminal phosphorylation is associated with myoblast activation: impairment in Emery–Dreifuss muscular dystrophy

V Cenni^2,*, P Sabatelli^1,*, E Mattioli², S Marmiroli⁴, C Capanni², A Ognibene², S Squarzoni¹, N M Maraldi¹, G Bonne⁵, M Columbaro³, L Merlini³, G Lattanzi¹

¹ ITOI, CNR, Unit of Bologna, c/o IOR, Bologna, Italy
² Laboratory of Cell Biology, Istituti Ortopedici Rizzoli, Bologna
³ Neuromuscular Unit, Istituti Ortopedici Rizzoli
⁴ Department of Morphological Science, University of Modena and Reggio Emilia, Italy
⁵ Inserm U582, Institut de myologie, Groupe Hospitalier Pitié-Salpétrière, Paris, France

Correspondence to:
Correspondence to:
Dr Giovanna Lattanzi
ITOI-CNR, Unit of Bologna, c/o IOR, Via di Barbiano 1/10, I-40136 Bologna, Italy; lattanzi{at}jolly.bo.cnr.it

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.

Abbreviations: EDMD, Emery–Dreifuss muscular dystrophy; LGMD 1B, limit girdle muscular dystrophy 1B

Keywords: Emery–Dreifuss muscular dystrophy; lamin A/C phosphorylation; limb girdle muscular dystrophy

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