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(Circulation Research. 1997;81:703-710.)
© 1997 American Heart Association, Inc.

Articles

Skeletal Muscle Sarcoplasmic Reticulum Ca²⁺-ATPase Gene Expression in Congestive Heart Failure

David G. Peters, Heather L. Mitchell, Sylvia A. McCune, Sonhee Park, Jay H. Williams, , Susan C. Kandarian

From the Department of Health Sciences (D.G.P., H.L.M., S.C.K.), Boston University, Boston, Mass; the Department of Food Science and Technology (S.A.M., S.P.), The Ohio State University, Columbus, Ohio; and the Department of Human Nutrition and Foods (J.H.W.), Virginia Polytech, Blacksburg, Va.

Correspondence to Susan Kandarian, PhD, Boston University, Department of Health Sciences, 635 Commonwealth Ave, Boston, MA 02215. E-mail skandar{at}acs.bu.edu

Abstract Congestive heart failure leads to skeletal muscle abnormalities, one of which is a prolongation of sarcoplasmic reticulum Ca²⁺ flux. The purpose of this study was to determine whether skeletal muscle of spontaneous hypertensive and heart failure rats have alterations in the expression of the sarcoplasmic (or endoplasmic) reticulum Ca²⁺-ATPase (SERCA) gene. Northern analysis revealed that SERCA1, the predominant skeletal muscle isoform, was decreased by 45%, 43%, and 58% in the tibialis anterior, plantaris, and diaphragm muscles, respectively. Ribonuclease protection assay showed that the decrease was due to the adult isoform, SERCA1a, with minor changes in the alternatively spliced neonatal isoform, SERCA1b. There was no change in SERCA1 mRNA levels in gastrocnemius muscles. No change was found in SERCA2a (cardiac/slow skeletal isoform) mRNA or protein levels or in SERCA2b (smooth muscle isoform), dihydropyridine receptor, or -actin mRNA levels in diaphragm muscle. Northern blot and ribonuclease protection assays showed that SERCA2a decreased 61% in the heart while the alternatively spliced isoform, SERCA2b, decreased 27%. Western analysis of the tibialis anterior, diaphragm, and gastrocnemius muscles showed a decrease in SERCA1 protein levels by 46%, 64%, and 42%, respectively, whereas sarcoplasmic reticulum Ca²⁺-ATPase activity, a functional correlate of SERCA expression, was decreased by 38%, 38%, and 40% in the same muscles. SERCA2 protein expression decreased by 36% in the failing heart. Decreases in both mRNA and protein suggest pretranslational control of SERCA1 expression, whereas the lack of decreased SERCA1 mRNA in gastrocnemius muscle suggests translational regulation. The decreased SERCA1 protein expression in all muscles studied probably contributes to contractile abnormalities related to excitation-contraction coupling function in heart failure.

Key Words: sarcoplasmic reticulum • skeletal muscle • heart failure

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