Contractile properties of myocardium are altered in dystrophin-deficient mdx mice.

The objective of this study was to determine whether cardiac contractile force is altered in the dystrophin-deficient mdx mouse model of muscular dystrophy. Left atria from 12-14-week-old control and mdx mice were paced at 1 Hz in 1.25 mM external Ca2+ buffer. Twitch properties and effects of interposing intervals of 0.3 to 600 s on the force of subsequent beats (force-interval curves) were examined. Peak force and time-to-peak force were similar in both groups, but half-relaxation time was significantly prolonged in mdx heart. In control hearts, force-interval curves increased to an inflection point at about 1 s, then rose to a second peak near 60 s. In mdx heart, curves reached the early inflection more quickly, the second peak was diminished in magnitude and force was greatly depressed at long intervals. Curves were fitted to a four-parameter equation to quantify differences in shape. The parameter a, which reflects rate of rise to the first inflection, was significantly increased in mdx atria, while the parameter B, which reflects amplitude of the late peak, was significantly reduced. These differences in force production were more marked when external Ca2+ was raised to 2.5 mM. Results show contractile properties are markedly altered in atria from dystrophin-deficient mdx mice. These findings are consistent with the hypothesis that dystrophin deficiency affects cardiac contractile function, possibly through effects on SR function.

Density of ryanodine receptors is increased in sarcoplasmic reticulum from prehypertrophic cardiomyopathic hamster heart.

Calcium overload has been linked to the development of cardiomyopathy in the cardiomyopathic (CM) hamster, but the site or sites of the lesion remain obscure. To determine whether the number of sarcoplasmic reticulum (SR) calcium release channels (ryanodine receptors) changes in the CM heart, we compared the density (Bmax) and affinity (Kd) of [3H]-ryanodine binding sites in heavy SR fractions from 40-65 day-old normal and CM hamster hearts. Results showed that the Bmax was significantly increased in CM heart when compared to normal (Bmax = 2489 +/- 159 fmol/mg protein in normal heart and 3360 +/- 223 fmol/mg protein in CM heart, mean +/- S.E., P = 0.01). [3H]-Ryanodine bound to a single, high affinity site in SR from both normal and CM hearts; values for Kd were similar in both groups. Sensitivity of [3H]-ryanodine binding to Ca2+ was unchanged, but the density of binding was increased at all Ca2+ concentrations which potentiated binding in CM heart. Similarly, potentiation of [3H]ryanodine binding by ATP and inhibition of binding by Mg2+ were intact in membranes from CM heart. Results demonstrate that the density [3H]-ryanodine receptors is increased in SR from CM hearts early in the development of cardiomyopathy, although the properties of these receptors are unchanged. This suggests an increase in the amount or velocity of Ca2+ release from SR may contribute to the development of Ca2+ overload in this model of cardiomyopathy.