Figure 5

Sarcospan is a critical regulator of laminin-binding receptors in muscle. (A) The DGC/UGC and α7β1 integrin at the sarcolemma in mdx^3.0 (SSPN-Tg:mdx) muscle is depicted. The dystroglycans (DGs; pink), sarcoglycans (SGs; yellow), sarcospan (SSPN; blue), dystrophin (grey) and integrins (purple) are shown. Overexpression of SSPN in mdx muscle elicits a series of molecular events that lead to restoration of laminin binding, amelioration of pathology, and restoration of membrane integrity [19]. As shown in the illustration, SSPN activates Akt, which stabilizes utrophin, and increases the abundance of integrin and WFA-reactive α-DG at the cell surface. SSPN facilitates increased CT antigen modification of α-DG and enhances transportation of utrophin-DG at the sarcolemma [19]. Collectively, these events lead to stabilization of the sarcolemmal membrane and amelioration of dystrophic pathology. (B) SSPN-null muscle exhibits decreased dystrophin and Akt activation followed by decreased expression of utrophin, resulting in the reduction of laminin-binding to α-DG (middle panel) [19]. Acute muscle injury by cardiotoxin injection into SSPN-null muscle impairs muscle regeneration (right) [19]. However, pre-treatment of SSPN-null mice with adenovirus containing constitutively active Akt (Ad-caAkt) restored the activation of downstream p70S6K, utrophin expression, and improved muscle regeneration (right panel). These studies reveal the importance of sarcospan and Akt in regulating utrophin expression that is critical for muscle repair. CT, cytotoxic T cell; DGC, dystrophin-glycoprotein complex; UGC, utrophin-glycoprotein complex; WFA, Wisteria floribunda agglutinin.