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This Article Full Text Full Text (PDF) All Versions of this Article: 584/3/997    most recent jphysiol.2007.141481v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by D'Antona, G. Articles by Bottinelli, R. Search for Related Content PubMed PubMed Citation Articles by D'Antona, G. Articles by Bottinelli, R. Related Collections Skeletal Muscle and Exercise

¹ Department of Experimental Medicine and Interuniversity Institute of Myology (IIM), Human Physiology Unit, University of Pavia, Pavia, Italy
² Department of Biomedical Sciences, University of Modena and Reggio Emilia, Italy

We recently generated a mouse model of facioscapulohumeral muscular dystrophy (FSHD) by selectively overexpressing FRG1, a candidate gene for FSHD, in skeletal muscle. The muscles of the FRG-1 mice did not show any plasmamembrane defect suggesting a novel pathogenetic mechanism for FSHD. Here, we study structure and function of muscle fibres from three lines of mice overexpressing FRG1 at different levels: FRG1-low, FRG1-med, FRG1-high. Cross-sectional area (CSA), specific force (Po/CSA) and maximum shortening velocity (V_o) of identified types of muscle fibres from FRG1-low and FRG1-med mice were analysed and found to be lower than in WT mice. Fast fibres and especially type 2B fibres (the fastest type) were preferentially involved in the dystrophic process showing a much larger force deficit than type 1 (slow) fibres. Consistent with the latter observation, the MHC isoform distribution of several muscles of the three FRG1 lines showed a shift towards slower MHC isoforms in comparison to WT muscle. Moreover, fast muscles showed a more evident histological deterioration, a larger atrophy and a higher percentage of centrally nucleated fibres than the soleus, the slowest muscle in mice. Interestingly, loss in CSA, Po/CSA and V_o of single muscle fibres and MHC isoform shift towards a slower phenotype can be considered early signs of muscular dystrophy (MD). They were, in fact, found also in FRG1-low mice which did not show any impairment of function in vivo and of muscle size in vitro and in soleus muscles, which had a completely preserved morphology. This study provides a detailed characterization of structure and function of muscle fibres in a novel murine model of one of the main human MDs and suggests that fundamental features of the dystrophic process, common to most MDs, such as the intrinsic loss of contractile strength of muscle fibres, the preferential involvement of fast fibres and the shift towards a slow muscle phenotype can occur independently from obvious alterations of the plasma membrane.

(Received 25 July 2007; accepted after revision 10 September 2007; first published online 13 September 2007)
Corresponding author G. D'Antona: Department of Experimental Medicine, Human Physiology Unit, University of Pavia, Via Forlanini 6, 27100 Pavia, Italy. Email: gdantona{at}unipv.it