期刊
HUMAN MOLECULAR GENETICS
卷 21, 期 20, 页码 4378-4393出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds271
关键词
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资金
- Genetic Mechanisms Pre-doctoral Training Fellowship USPHS National Research Service Award [GM07104]
- Edith Hyde Fellowship
- Eureka Pre-doctoral Training Fellowship
- Undergraduate Research Fellows Program
- National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin [R01 AR053697, R01 AR048179]
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 71 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 7 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.
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