Abstract 314: Loss of Sarcospan has a Deleterious Effect on Cardiac Function in Aged Mice
Sarcospan (SSPN) has been shown to have an important role in stabilizing sarcolemmal dystrophin- and utrophin-glycoprotein adhesion complexes. Loss of sarcolemmal integrity leads to immune cell infiltration and inappropriate exchange of cellular contents with the extracellular milieu. Our laboratory has shown SSPN loss destabilizes skeletal muscle adhesion and reduces sarcolemmal dystrophin localization, whereas its complete loss due to mutation underlies development of Duchenne muscular dystrophy (DMD). Loss of dystrophin leads to cardiac dysfunction and early mortality in DMD patients. The role of SSPN in the heart is unknown. We present immunofluorescence data revealing reduction of dystrophin and the sarcoglycans with a coordinate increase of β1D integrin levels at the SSPN-null cardiac sarcolemma relative to WT. Also, SSPN loss decreases cardiac P-Akt levels, disrupting signaling promoting compensatory physiological hypertrophy. These studies suggest a fundamental role for SSPN in cardiac maintenance and function, since left ventricular mass increases with age and upon isoproterenol administration (0.8 mg/day for two wks). Aged SSPN-null mice developed hypertrophy, evidenced as increased heart/body weight ratio and left ventricular wall dimension. The SSPN-null mice lacked the characteristic initial rise in cardiac output, left ventricular ejection fraction (LvEF %), induced by chronic β-adrenergic stimulation. Functionally, aged SSPN-null hearts had an increased E/A ratio indicating restrictive ventricular filling and decreased fractional shortening F/S (%) upon isoproterenol administration. Aged untreated SSPN-null hearts had increased fibrosis compared to aged WT controls, however isoproterenol treated SSPN-null hearts displayed exacerbated fibrotic response compared to WT. To assess whether SSPN-null hearts have altered gene expression profiles during progression of pathogenesis, qRT-PCR will be utilized to measure differences in expression of fetal gene and calcium-handling proteins. In summary, we have found that SSPN has an important role in maintaining cardiac function, its loss exacerbates the hypertrophic response and localization of stabilizing adhesion complexes at the cardiac muscle sarcolemma.
Author Disclosures: M.S. Parvatiyar: None J.L. Marshall: None M.C. Jordan: None R.T. Nguyen: None K.P. Roos: None R.H. Crosbie-Watson: None.
- © 2014 by American Heart Association, Inc.