title: Gamma-sarcoglycan is required for the response of archvillin to mechanical stimulation in skeletal muscle.
abstract: Loss of gamma-sarcoglycan (γ-SG) induces muscle degeneration and signaling defects in response to mechanical load, and its absence is common to both Duchenne and limb girdle muscular dystrophies. Growing evidence suggests that aberrant signaling contributes to the disease pathology; however, the mechanisms of γ-SG-mediated mechanical signaling are poorly understood. To uncover γ-SG signaling pathway components, we performed yeast two-hybrid screens and identified the muscle-specific protein archvillin as a γ-SG and dystrophin interacting protein. Archvillin protein and message levels were significantly upregulated at the sarcolemma of murine γ-SG-null (gsg(-/-)) muscle but delocalized in dystrophin-deficient mdx muscle. Similar elevation of archvillin protein was observed in human quadriceps muscle lacking γ-SG. Reintroduction of γ-SG in gsg(-/-) muscle by rAAV injection restored archvillin levels to that of control C57 muscle. In situ eccentric contraction of tibialis anterior (TA) muscles from C57 mice caused ERK1/2 phosphorylation, nuclear activation of P-ERK1/2 and stimulus-dependent archvillin association with P-ERK1/2. In contrast, TA muscles from gsg(-/-) and mdx mice exhibited heightened P-ERK1/2 and increased nuclear P-ERK1/2 localization following eccentric contractions, but the archvillin-P-ERK1/2 association was completely ablated. These results position archvillin as a mechanically sensitive component of the dystrophin complex and demonstrate that signaling defects caused by loss of γ-SG occur both at the sarcolemma and in the nucleus.
authors.affiliation: Department of Anatomy and Cell Biology, School of Dental Medicine, Pennsylvania Muscle Institute, and.
authors.forename: Janelle M
authors.initials: JM
authors.lastname: Spinazzola
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Tara C
authors.initials: TC
authors.lastname: Smith
authors.affiliation: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA and.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Luna
authors.affiliation: Department of Anatomy and Cell Biology, School of Dental Medicine, Pennsylvania Muscle Institute, and erbarton@ufl.edu.
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: Barton
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D016189:Dystrophin / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D049031:Sarcoglycans / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013314:Stress, Mechanical; D020798:Two-Hybrid System Techniques
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008565:Membrane Proteins; D008840:Microfilament Proteins; C109413:SVIL protein, human; D049031:Sarcoglycans; C491615:Svil protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3