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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Neural agrin controls maturation of the excitation-contraction coupling mechanism in human myotubes developing in vitro

Elena Bandi,^1,4 Marko Jevek,³ Tomaz Mars,³ Mihaela Jurdana,¹ Elena Formaggio,² Marina Sciancalepore,¹ Guido Fumagalli,² Zoran Grubi,³ Fabio Ruzzier,¹ and Paola Lorenzon¹

¹Department of Physiology and Pathology and Centre for Neuroscience B.R.A.I.N., University of Trieste, Trieste; ²Department of Medicine and Public Health, University of Verona, Hospital Borgo Roma, Verona, Italy; ³Institute of Pathophysiology, School of Medicine, University of Ljubljana, Ljubljana, Slovenia; and ⁴Interdepartmental Centre of Molecular Medicine, University of Trieste, Trieste, Italy

Submitted 12 June 2007 ; accepted in final form 12 November 2007

The aim of this study was to elucidate the mechanisms responsible for the effects of innervation on the maturation of excitation-contraction coupling apparatus in human skeletal muscle. For this purpose, we compared the establishment of the excitation-contraction coupling mechanism in myotubes differentiated in four different experimental paradigms: 1) aneurally cultured, 2) cocultured with fetal rat spinal cord explants, 3) aneurally cultured in medium conditioned by cocultures, and 4) aneurally cultured in medium supplemented with purified recombinant chick neural agrin. Ca²⁺ imaging indicated that coculturing human muscle cells with rat spinal cord explants increased the fraction of cells showing a functional excitation-contraction coupling mechanism. The effect of spinal cord explants was mimicked by treatment with medium conditioned by cocultures or by addition of 1 nM of recombinant neural agrin to the medium. The treatment with neural agrin increased the number of human muscle cells in which functional ryanodine receptors (RyRs) and dihydropyridine-sensitive L-type Ca²⁺ channels were detectable. Our data are consistent with the hypothesis that agrin, released from neurons, controls the maturation of the excitation-contraction coupling mechanism and that this effect is due to modulation of both RyRs and L-type Ca²⁺ channels. Thus, a novel role for neural agrin in skeletal muscle maturation is proposed.

neurotrophic factor; calcium homeostasis; differentiation; skeletal muscle