Abnormal Skeletal Muscle Regeneration plus Mild Alterations in Mature Fiber Type Specification in Fktn-Deficient Dystroglycanopathy Muscular Dystrophy Mice

• Published in: PloS one Vol. 11; no. 1; p. e0147049
• Main Authors: Foltz, Steven J, Modi, Jill N, Melick, Garrett A, Abousaud, Marin I, Luan, Junna, Fortunato, Marisa J, Beedle, Aaron M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.01.2016; Public Library of Science (PLoS)
• Subjects: Abnormalities; Animals; Cardiotoxins - chemistry; Chains; Clonal deletion; Congenital diseases; Cytoskeleton; Degeneration; Disease; Disease Models, Animal; Divergence; Dystroglycan; Dystroglycans - genetics; Dystroglycans - metabolism; Dystrophin; Dystrophy; Embryos; Exons; Extracellular matrix; Fibers; Gene Deletion; Genotype; Genotypes; Glycan; Glycoproteins; Glycosylation; Injuries; Laminin; Laminin - metabolism; Mannose; Mice; Mice, Knockout; Muscle Fibers, Skeletal - physiology; Muscle, Skeletal - physiology; Muscles; Muscular dystrophy; Muscular Dystrophy, Animal - genetics; Muscular Dystrophy, Animal - metabolism; Musculoskeletal system; Myosin; Necrosis; Pharmaceuticals; Physiological aspects; Proteins; Proteins - genetics; Regeneration; Rodents; Signal Transduction; Signaling; Skeletal muscle; Specifications; Structural integrity; Tamoxifen; United States; United States > US; Georgia; Des Moines Iowa
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0147049

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.