title: Abnormal Skeletal Muscle Regeneration plus Mild Alterations in Mature Fiber Type Specification in Fktn-Deficient Dystroglycanopathy Muscular Dystrophy Mice.
abstract: Glycosylated α-dystroglycan provides an essential link between extracellular matrix proteins, like laminin, and the cellular cytoskeleton via the dystrophin-glycoprotein complex. In secondary dystroglycanopathy muscular dystrophy, glycosylation abnormalities disrupt a complex O-mannose glycan necessary for muscle structural integrity and signaling. Fktn-deficient dystroglycanopathy mice develop moderate to severe muscular dystrophy with skeletal muscle developmental and/or regeneration defects. To gain insight into the role of glycosylated α-dystroglycan in these processes, we performed muscle fiber typing in young (2, 4 and 8 week old) and regenerated muscle. In mice with Fktn disruption during skeletal muscle specification (Myf5/Fktn KO), newly regenerated fibers (embryonic myosin heavy chain positive) peaked at 4 weeks old, while total regenerated fibers (centrally nucleated) were highest at 8 weeks old in tibialis anterior (TA) and iliopsoas, indicating peak degeneration/regeneration activity around 4 weeks of age. In contrast, mature fiber type specification at 2, 4 and 8 weeks old was relatively unchanged. Fourteen days after necrotic toxin-induced injury, there was a divergence in muscle fiber types between Myf5/Fktn KO (skeletal-muscle specific) and whole animal knockout induced with tamoxifen post-development (Tam/Fktn KO) despite equivalent time after gene deletion. Notably, Tam/Fktn KO retained higher levels of embryonic myosin heavy chain expression after injury, suggesting a delay or abnormality in differentiation programs. In mature fiber type specification post-injury, there were significant interactions between genotype and toxin parameters for type 1, 2a, and 2x fibers, and a difference between Myf5/Fktn and Tam/Fktn study groups in type 2b fibers. These data suggest that functionally glycosylated α-dystroglycan has a unique role in muscle regeneration and may influence fiber type specification post-injury.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Foltz
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Jill N
authors.initials: JN
authors.lastname: Modi
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Garrett A
authors.initials: GA
authors.lastname: Melick
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Marin I
authors.initials: MI
authors.lastname: Abousaud
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Junna
authors.initials: J
authors.lastname: Luan
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Marisa J
authors.initials: MJ
authors.lastname: Fortunato
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Beedle
mesh_terms: D000818:Animals; D054715:Cardiotoxins / Q000737:chemistry; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D017353:Gene Deletion; D005838:Genotype; D006031:Glycosylation; D007797:Laminin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D018482:Muscle, Skeletal / Q000502:physiology; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000378:metabolism; D009336:Necrosis; D011506:Proteins / Q000235:genetics*; D012038:Regeneration; D015398:Signal Transduction; D014166:Transferases
chemical_list: D054715:Cardiotoxins; D007797:Laminin; D011506:Proteins; D049030:Dystroglycans; C491879:Fcmd protein, mouse; D014166:Transferases