Rabbit skeletal muscle sarcoplasmic reticulum Ca 2+-ATPase activity: stimulation in vitro by thyroid hormone analogues and bipyridines

Abstract

Sarcoplasmic reticulum-enriched membranes from rabbit skeletal muscle contained Ca 2+-ATPase activity which was significantly enhanced (26% increase, P < 0.001) in vitro by physiological concentrations (10 −10 M) of L-thyroxine (T 4) and 3,3′,5-triiodo- L-thyronine (T 3). In contrast, the biologically inactive iodothyronine analogues D-T 4 and 3,3′,5,5′-tetraiodothyroacetic acid (Tetrac) (10 −10 M) were without effect on enzyme activity. 3,5-Dimethyl-3′-isopropyl- L-thyronine (Dimit), a bioactive analogue, was highly effective as a Ca 2+-ATPase stimulator, increasing enzyme activity by 43% ( P < 0.02 vs. T 4 effect). A bipyridine cardiac inotropic agent, milrinone, has been reported to be thyromimetic in a myocardial membrane Ca 2+-ATPase system, and in concentrations from 10 −10 to 10 −5 M enhanced skeletal muscle SR membrane Ca 2+-ATPase activity in vitro ( P < 0.001). Milrinone analogues which have been previously shown to enhance rabbit myocardial membrane Ca 2+-ATPase activity, and which have a twist relationship of the pyridine rings, were also striated muscle Ca 2+-ATPase stimulators. We conclude that (1) striated muscle is a mammalian tissue in which physiological levels of biologically relevant thyroid hormone analogues, particularly Dimit, stimulate Ca 2+-ATPase activity in vitro by a non-genomic mechanism; (2) cardiac bipyridine analogues which are thyromimetic in vitro in rabbit heart, and which have structural homologies with thyroid hormone, are stimulators of rabbit striated muscle sarcoplasmic reticulum Ca 2+-ATPase activity.