A Subpopulation of Rat Muscle Fibers Maintains an Assessable Excitation-Contraction Coupling Mechanism After Long-Standing Denervation Despite Lost Contractility

Authors:Squecco R1,2, Carraro U1,3,4, Kern H5, Pond A6, Adami N1,3, Biral D4, Vindigni V4, Boncompagni S1,6, Pietrangelo T1,6, Bosco G1,6, Fanò G1,6, Marini M1,7, Abruzzo P1,8, Germinario E1,9, Danieli-Betto D1,9, Protasi F1,7, Francini F1,2, Zampieri S1,4,10

Source: J Neuropathol Exp Neurol. 2009 Dec;68(12):1256-68.

Keywords: Excitation-contraction coupling, DHPR, RYR-1 Ca2+ channels, Gene expression, L-Type Ca2+ current,
Long-term denervation, Sarcotubular system


To define the time course and potential effects of electrical stimulation on permanently denervated muscle, we evaluated excitation-contraction coupling (ECC) of rat leg muscles during progression to long-term denervation by ultrastructural analysis, specific binding to dihydropyridine receptors, ryanodine receptor 1 (RYR-1), Ca channels and extrusion Ca pumps, gene transcription and translation of Ca-handling proteins, and in vitro mechanical properties and electrophysiological analyses of sarcolemmal passive properties and L-type Ca current (ICa) parameters. We found that in response to long-term denervation: 1) isolated muscle that is unable to twitch in vitro by electrical stimulation has very small myofibers but may show a slow caffeine contracture; 2) only roughly half of the muscle fibers with "voltage-dependent Ca channel activity" are able to contract; 3) the ECC mechanisms are still present and, in part, functional; 4)ECC-related gene expression is upregulated; and 5) at any time point, there are muscle fibers that are more resistant than others to denervation atrophy and disorganization of the ECC apparatus. These results support the hypothesis that prolonged "resting" [Ca] may drive progression of muscle atrophy to degeneration and that electrical stimulation-induced [Ca] modulation may mimic the lost nerve influence, playing a key role in modifying the gene expression of denervated muscle. Hence, these data provide a potential molecular explanation for the muscle recovery that occurs in response to rehabilitation strategies developed based on empirical clinical observations.


1 Interuniversitary Institute of Myology, Chieti
2 Department of Physiological Sciences, University of Florence, Florence
3 Lab. of Translational Myology of the University of Padova Interdepartmental Research Center of Myology, c/o Department of Biomedical Sciences, Padova
4 Italian C.N.R. Institute of Neuroscience, University
of Padova
5 Ludwig Boltzmann Institute of Electrostimulation and Physical Rehabilitation, Department of Physical Medicine, Wilhelminenspital, Vienna, Austria
6 Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, Indiana
7 Department of Basic and Applied Medical Sciences, CeSI-Centro Scienze dell’Invecchiamento, University G. d’Annunzio, Chieti
8 Department of Histology, Embryology and Applied Biology, University of Bologna, Bologna
9 Department of Anatomy and Physiology, University of Padova, Padova, Italy
10 Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy