Severe food restriction induces myocardial dysfunction related to SERCA2 activity

Previous studies have shown that food restriction promotes myocardial dysfunction in rats. However, the molecular mechanisms that are responsible are unclear. We investigated the role of sarcoplasmic reticulum [Ca.sup.2+]-ATPase (SERCA2) on myocardial performance in food-restricted rats. Male Wistar-Kyoto rats, 60 days old, were fed a control or restricted diet (daily energy intake reduced to 50% of the control) for 90 days. Expression of Serca2a, phospholamban (PLB), [NA.sup.2+]/[Ca.sup.2+] exchanger (NCX), and thyroid hormone receptor (TRα1, TRβ1) mRNA was determined by quantitative PCR. SERCA2 activity was measured by using 20 µmol/L cyclopiazonic acid (CPA) in a left ventricular papillary muscle preparation during isometric contraction in basal conditions and during post-rest contraction. Serum concentrations of thyroxine ([T.sub.4]) and thyrotropin (TSH) were also determined. The 50%-restricted diet reduced body and ventricular weight and serum [T.sub.4] and TSH levels. The interaction of CPA and food restriction reduced peak developed tension and maximum rate of tension decline (-dT/dt), but increased the resting tension intensity response during post-rest contraction. PLB and NCX mRNA were upregulated and TRα1 mRNA was downregulated by food restriction. These results suggest that food restriction promotes myocardial dysfunction related to impairment of sarcoplasmic reticulum [Ca.sup.2+] uptake as a result of a hypothyroid state. Key words: SERCA2, cyclopiazonic acid, calcium handling, food restriction, rats, myocardial function, thyroid hormone. Des etudes arterieures revelent que la restriction alimentaire suscite des dysfonctions myocardiques chez le rat. Cependant, on n'en connait pas bien les mecanismes moleculaires. On a analyse le role de la SERCA2 sur la performance myocardique de rats soumis a une restriction alimentaire. Des rats Wistar-Kyoto males ages de 60 jours sont diviseesen deux groupes, l'un de controle et l'autre, soumis a une restriction alimentaire consistant a ingeerer 50 % de l'apport du groupe de controle, et ce, durant 90 jours. On determine l'expression de la SERCA2,de la PLB, de l'eechangeur [NA.sup.2+]/[Ca.sup.2+] (NCX), de l'ARNm des recepteurs des hormones thyroidiennes (TRα1, TRβ1) par la quantification de la PCR. On mesure l'activite de la SERCA2 au moyen de 20 µmol/L d'acide cyclopiazonique (CPA) dans une preparation de muscle papillaire du ventricule gauche (LV) au cours d'une contraction isomeetrique dans des conditions de repos et a la suite d'une contraction post-repos. On evalue aussi les concentrations de [T.sub.4] et de TSH. Le regime avec restriction a 50 % suscite une diminution de la masse corporelle et de la masse du ventricule; les concentrations seriques de [T.sub.4] et de TSH diminuent. L'interaction du CPA et de la restriction alimentaire diminue DT et -dT/dt, mais augmente l'intensite de la reponse RT au cours de la contraction post-repos. La restriction alimentaire suscite une regulation a la hausse de l'ARNm de NCX et de la PLB, mais une regulation a la baisse de l'ARNm de TRα1. D'apres ces observations, la restriction alimentaire favorise la dysfonction du myocarde associeea la deterioration dans le reticulum sarcoplasmique de la captation du [Ca.sup.2+] causeee par l'etat hypothyroidien. Mots-cles: SERCA2, acide cyclopiazonique, prise en charge du calcium, restriction alimentaire, rats, fonction myocardique, hormone thyroidienne. [Traduit par la Redaction]
Introduction Food restriction increases the maximum life span of rats (Berner and Stern 2004; Keenan et al. 1996) and slows or prevents a broad spectrum of age-related pathophysiological changes, such [...]