G.P.18 Muscle pathology and dysfunction in a novel mouse model of COLVI-myopathy

Abstract

Collagen VI-myopathies regroup several forms of neuromuscular disorders caused by the deficiency of collagen type VI (COLVI), a protein that contributes to the architectural structure of muscle, its maintenance and survival. COLVI-myopathies constitute a spectrum of clinical presentations ranging from severe, early-onset phenotypes, to intermediate and milder phenotypes, with Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy at each extremity. To investigate in details the pathogenesis and to evaluate therapeutic strategies, we developed a novel mouse model carrying a nonsense mutation in the Col6a2 gene, based on the mutation identified in a patient with classical UCMD. Overall, homozygous KI-Col6a2 animals (KI) are viable and fertile, but males fail to thrive and display a significantly reduced body weight compared to wild type and heterozygous littermates, detectable as early as 4weeks of age. We examined in detail the skeletal muscle phenotype of the KI-Col6a2 mice in terms of histology, morphology and function. The mutation introduced leads to a premature termination codon which triggers the specific degradation of the Col6a2 transcript through the nonsense-mediated RNA decay and the absence of COLVI in skeletal muscle from KI animals. These mice develop a myopathic phenotype with pronounced fiber size variability, increased internal nuclei and fibrosis. In addition, Tibialis anterior (TA) muscles of KI animals display significant hypoplasia, associated with an increase in type IIA fibers and a decrease in type IIB fibers. Accordingly, SDH and COX assays revealed more abundant oxidative fibers. At the functional level, the maximal specific force of TA muscle is significantly diminished in 9week-old KI males. Taken together, these data validate the KI-Col6a2 mouse as a model of COLVI-myopathy and identify quantifiable markers of muscle dysfunction that will be extremely useful to assess the potential benefit of therapeutic approaches.