title: Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse.
abstract: Muscular dystrophy is characterized by progressive skeletal muscle weakness and dystrophic muscle exhibits degeneration and regeneration of muscle cells, inflammation and fibrosis. Skeletal muscle fibrosis is an excessive deposition of components of the extracellular matrix including an accumulation of Collagen VI. We hypothesized that a reduction of Collagen VI in a muscular dystrophy model that presents with fibrosis would result in reduced muscle pathology and improved muscle function. To test this hypothesis, we crossed γ-sarcoglycan-null mice, a model of limb-girdle muscular dystrophy type 2C, with a Col6a2-deficient mouse model. We found that the resulting γ-sarcoglycan-null/Col6a2Δex5 mice indeed exhibit reduced muscle pathology compared with γ-sarcoglycan-null mice. Specifically, fewer muscle fibers are degenerating, fiber size varies less, Evans blue dye uptake is reduced and serum creatine kinase levels are lower. Surprisingly, in spite of this reduction in muscle pathology, muscle function is not significantly improved. In fact, grip strength and maximum isometric tetanic force are even lower in γ-sarcoglycan-null/Col6a2Δex5 mice than in γ-sarcoglycan-null mice. In conclusion, our results reveal that Collagen VI-mediated fibrosis contributes to skeletal muscle pathology in γ-sarcoglycan-null mice. Importantly, however, our data also demonstrate that a reduction in skeletal muscle pathology does not necessarily lead to an improvement of skeletal muscle function, and this should be considered in future translational studies.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: de Greef
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hamlyn
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Braden S
authors.initials: BS
authors.lastname: Jensen
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: O'Campo Landa
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Levy
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kobuke
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology and Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA kevin-campbell@uiowa.edu.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
mesh_terms: D000818:Animals; D024142:Collagen Type VI / Q000378:metabolism*; D015536:Down-Regulation; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009137:Muscular Dystrophy, Animal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D058088:Sarcoglycanopathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: C000613552:COL6A2 protein, mouse; D024142:Collagen Type VI