Changes in metabolic profile and population of skeletal muscle fibers of mice overexpressing calsequestrin: influence of losartan

Abstract

In heart failure, exertional fatigue of skeletal muscles can occur. A transgenic mouse overexpressing calsequestrin can be regarded as an animal model of heart failure. The aims of the present study were to investigate, whether at the time of cardiac failure the composition of fiber types of skeletal muscles was altered, what kind of alterations in glycolytic and oxidative enzyme activities occurred in different muscle fiber types and whether these were affected by the administration of the angiotensin II receptor blocker, losartan. Hemodynamic parameters were determined using a working heart preparation. Four groups of mice were investigated: wild-type (WT) mice and transgenic (TG) mice overexpressing calsequestrin, with and without losartan treatment. Enzyme activities were measured in homogenates of Rectus femoris muscle and in muscle fibers, which were typed by their metabolic profile. Calcineurin expression was measured by Western blotting. Succinate dehydrogenase activity was increased by 275% in R. femoris muscle homogenates of TG compared to WT mice. This was due to a 57% increase in slow oxidative fibers, which was accompanied by an increased calcineurin expression in TG muscles. This increase was attenuated by losartan treatment. With respect to glycerol-3-phosphate-dehydrogenase (GPDH), no difference was evident comparing WT and TG. Treatment with losartan resulted in a down-regulation of GPDH in WT and TG. In conclusion, changes in skeletal muscles occur in this mouse model of heart failure and these changes were antagonized by losartan. In contrast to heart failure patients, in the mouse model a shift to the oxidative phenotype of skeletal muscle was noted, possibly due to enhanced calcineurin expression.