title: Viral-mediated expression of desmin mutants to create mouse models of myofibrillar myopathy.
abstract: BACKGROUND
  The clinical features of myofibrillar myopathies display a wide phenotypic heterogeneity. To this date, no studies have evaluated this parameter due to the absence of pertinent animal models. By studying two mutants of desmin, which induce subtle phenotypic differences in patients, we address this issue using an animal model based on the use of adeno-associated virus (AAV) vectors carrying mutated desmin cDNA.
  
  
  METHODS
  After preparation of the vectors, they were injected directly into the tibialis anterior muscles of C57BL/6 mice to allow expression of wild-type (WT) or mutated (R406W or E413K) desmin. Measurements of maximal force were carried out on the muscle in situ and then the injected muscles were analyzed to determine the structural consequences of the desmin mutations on muscle structure (microscopic observations, histology and immunohistochemistry).
  
  
  RESULTS
  Injection of AAV carrying WT desmin results in the expression of exogenous desmin in 98% of the muscle fibers without any pathological or functional perturbations. Exogenous WT and endogenous desmin are co-localized and no differences were observed compared to non-injected muscle. Expression of desmin mutants in mouse muscles induce morphological changes of muscle fibers (irregular shape and size) and the appearance of desmin accumulations around the nuclei (for R406W) or in subsarcolemmal regions of fibers (for E413K). These accumulations seem to occur and disrupt the Z-line, and a strong regeneration was observed in muscle expressing the R406W desmin, which is not the case for E413K. Moreover, both mutants of desmin studied here induce a decrease in muscle force generation capacity.
  
  
  CONCLUSIONS
  In this study we show that AAV-mediated expression of desmin mutants in mouse muscles recapitulate the aggregation features, the decrease in contractile function and the morphological changes observed in patients with myofibrillar myopathy. More importantly, our results suggest that the R406W desmin mutant induces a robust muscle regeneration, which is not the case for the E413K mutant. This difference could help to explain the phenotypic differences observed in patients. Our results highlight the heterogeneous pathogenic mechanisms between different desmin mutants and open the way for new advances in the study of myofibrillar myopathies.
authors: Université Paris Diderot, Sorbonne Paris Cité, CNRS EAC4413, Unit of Functional and Adaptive Biology, Laboratory of Stress and Pathologies of the Cytoskeleton, 75013, Paris, France.
authors: Pierre
authors: P
authors: Joanne
authors: Université Paris Diderot, Sorbonne Paris Cité, CNRS EAC4413, Unit of Functional and Adaptive Biology, Laboratory of Stress and Pathologies of the Cytoskeleton, 75013, Paris, France.
authors: Oussama
authors: O
authors: Chourbagi
authors: Department of Aging, Stress and Inflammation, Université Pierre et Marie Curie-Paris 6, Sorbonne Universités, 75005, Paris, France.
authors: Christophe
authors: C
authors: Hourdé
authors: Université Pierre et Marie Curie-Paris 6, Sorbonne Universités, UMR S794, INSERM U974, CNRS UMR7215, Institut de Myologie, 75013, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, 75006, Paris, France.
authors: Arnaud
authors: A
authors: Ferry
authors: Université Pierre et Marie Curie-Paris 6, Sorbonne Universités, UMR S794, INSERM U974, CNRS UMR7215, Institut de Myologie, 75013, Paris, France.
authors: Gillian
authors: G
authors: Butler-Browne
authors: Université Paris Diderot, Sorbonne Paris Cité, CNRS EAC4413, Unit of Functional and Adaptive Biology, Laboratory of Stress and Pathologies of the Cytoskeleton, 75013, Paris, France.
authors: Patrick
authors: P
authors: Vicart
authors: Université Pierre et Marie Curie-Paris 6, Sorbonne Universités, UMR S794, INSERM U974, CNRS UMR7215, Institut de Myologie, 75013, Paris, France.
authors: Julie
authors: J
authors: Dumonceaux
authors: Université Paris Diderot, Sorbonne Paris Cité, CNRS EAC4413, Unit of Functional and Adaptive Biology, Laboratory of Stress and Pathologies of the Cytoskeleton, 75013, Paris, France.
authors: Onnik
authors: O
authors: Agbulut