Dlk1 is necessary for proper skeletal muscle development and regeneration

• Published in: PloS one Vol. 5; no. 11; p. e15055
• Main Authors: Waddell, Jolena N, Zhang, Peijing, Wen, Yefei, Gupta, Sanjay K, Yevtodiyenko, Aleksey, Schmidt, Jennifer V, Bidwell, Christopher A, Kumar, Ashok, Kuang, Shihuan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.11.2010; Public Library of Science (PLoS)
• Subjects: Ablation; Analysis; Animal models; Animal sciences; Animals; Biology; Blotting, Western; Body weight; Cell Differentiation; Cell Line; Cell Proliferation; Cell self-renewal; Cells (biology); Cells, Cultured; Cervical cancer; Cytokines; Developmental biology; Differentiation; Drosophila; Epidermal growth factor; Gene expression; Growth rate; Hypertrophy; Immunohistochemistry; Inflammation; Insects; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Mammals; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - metabolism; Muscle proteins; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiology; Muscles; Muscular dystrophy; Musculoskeletal system; Myoblasts; Myoblasts - cytology; Myoblasts - metabolism; MyoD protein; MyoD Protein - genetics; MyoD Protein - metabolism; Myogenesis; Myosin; Neurobiology; Neurosciences; NF-κB protein; Overexpression; Preadipocyte factor 1; Regeneration; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Satellite cells; Satellite Cells, Skeletal Muscle - cytology; Satellite Cells, Skeletal Muscle - metabolism; Satellites; Signaling; Skeletal muscle; Stem cell transplantation; Stem cells; Urban regeneration; Weight reduction; Indiana; United States > US; Kentucky
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0015055

Delta-like 1homolog (Dlk1) is an imprinted gene encoding a transmembrane protein whose increased expression has been associated with muscle hypertrophy in animal models. However, the mechanisms by which Dlk1 regulates skeletal muscle plasticity remain unknown. Here we combine conditional gene knockout and over-expression analyses to investigate the role of Dlk1 in mouse muscle development, regeneration and myogenic stem cells (satellite cells). Genetic ablation of Dlk1 in the myogenic lineage resulted in reduced body weight and skeletal muscle mass due to reductions in myofiber numbers and myosin heavy chain IIB gene expression. In addition, muscle-specific Dlk1 ablation led to postnatal growth retardation and impaired muscle regeneration, associated with augmented myogenic inhibitory signaling mediated by NF-κB and inflammatory cytokines. To examine the role of Dlk1 in satellite cells, we analyzed the proliferation, self-renewal and differentiation of satellite cells cultured on their native host myofibers. We showed that ablation of Dlk1 inhibits the expression of the myogenic regulatory transcription factor MyoD, and facilitated the self-renewal of activated satellite cells. Conversely, Dlk1 over-expression inhibited the proliferation and enhanced differentiation of cultured myoblasts. As Dlk1 is expressed at low levels in satellite cells but its expression rapidly increases upon myogenic differentiation in vitro and in regenerating muscles in vivo, our results suggest a model in which Dlk1 expressed by nascent or regenerating myofibers non-cell autonomously promotes the differentiation of their neighbor satellite cells and therefore leads to muscle hypertrophy.