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Dystrophin and utrophin expression require sarcospan: loss of α7 integrin exacerbates a newly discovered muscle phenotype in sarcospan-null mice
- Source :
- Human Molecular Genetics. 21:4378-4393
- Publication Year :
- 2012
- Publisher :
- Oxford University Press (OUP), 2012.
-
Abstract
- Sarcospan (SSPN) is a core component of the major adhesion complexes in skeletal muscle, the dystrophin- and utrophin (Utr)-glycoprotein complexes (DGC and UGC). We performed a rigorous analysis of SSPN-null mice and discovered that loss of SSPN decreased DGC and UGC abundance, leading to impaired laminin-binding activity and susceptibility to eccentric contraction-induced injury in skeletal muscle. We show that loss of SSPN increased levels of α7β1 integrin. To genetically test whether integrin compensates for the loss of DGC and UGC function in SSPN-nulls, we generated mice lacking both SSPN and α7 integrin (DKO, double knockout). Muscle regeneration, sarcolemma integrity and fibrosis were exacerbated in DKO mice and were remarkably similar to muscle from Duchenne muscular dystrophy (DMD) patients, suggesting that secondary loss of integrin contributes significantly to pathogenesis. Expression of the DGC and UGC, laminin binding and Akt signaling were negatively impacted in DKO muscle, resulting in severely diminished specific force properties. We demonstrate that SSPN is a necessary component of dystrophin and Utr function and that SSPN modulation of integrin signaling is required for extracellular matrix attachment and muscle force development.
- Subjects :
- Male
Utrophin
Duchenne muscular dystrophy
Sarcospan
Dystrophin
Dystrophin-associated glycoprotein complex
Mice
Sarcolemma
Antigens, CD
Genetics
medicine
Animals
Muscular dystrophy
Muscle, Skeletal
Laminin binding
Molecular Biology
Genetics (clinical)
Mice, Knockout
biology
Membrane Proteins
Skeletal muscle
Articles
General Medicine
medicine.disease
Molecular biology
Neoplasm Proteins
Cell biology
Muscular Dystrophy, Duchenne
Disease Models, Animal
Phenotype
medicine.anatomical_structure
biology.protein
Female
Carrier Proteins
Integrin alpha Chains
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....c336aeae793e62fd0418c601fdf633ab