SKELETAL-MUSCLE SARCOPLASMIC-RETICULUM CA2-ATPASE GENE-EXPRESSION IN CONGESTIVE-HEART-FAILURE()

Congestive heart failure leads to skeletal muscle abnormalities, one o f which is a prolongation of sarcoplasmic reticulum Ca2+ flux. The pur pose of this study was to determine whether skeletal muscle of spontan eous hypertensive and heart failure rats have alterations in the expre ssion of the sarcoplasmic (or endoplasmic) reticulum Ca2+-ATPase (SERC A) gene. Northern analysis revealed that SERCA1, the predominant skele tal muscle isoform, was decreased by 45%, 43%, and 58% in the tibialis anterior, plantaris, and diaphragm muscles, respectively. Ribonucleas e protection assay showed that the decrease was due to the adult isofo rm, SERCA1a, with minor changes in the alternatively spliced neonataI isoform, SERCA1b. There was no change in SERCA1 mRNA levels in gastroc nemius muscles. No change was found in SERCA2a (cardiac/slow skeletal isoform) mRNA or protein levels or in SERCA2b (smooth muscle isoform), dihydropyridine receptor, or alpha-actin mRNA levels in diaphragm mus cle. Northern blot and ribonuclease protection assays showed that SERC A2a decreased 61% in the heart while the alternatively spliced isoform , SERCA2b, decreased 27%. Western analysis of the tibialis anterior, d iaphragm, and gastrocnemius muscles showed a decrease in SERCA1 protei n levels by 46%, 64%, and 42%, respectively, whereas sarcoplasmic reti culum Ca2+-ATPase activity, a functional correlate of SERCA expression , was decreased by 38%, 38%, and 40% in the same muscles. SERCA2 prote in expression decreased by 36% in the failing heart. Decreases in both mRNA and protein suggest pretranslational control of SERCA1 expressio n, whereas the lack of decreased SERCA1 mRNA in gastrocnemius muscle s uggests translational regulation. The decreased SERCA1 protein express ion in all muscles studied probably contributes to contractile abnorma lities related to excitation-contraction coupling function in heart fa ilure.