Effect of nonworking heterotopic transplantation on rat heart glycogen metabolism

To determine whether the contractile work history of cardiac muscle influences its responsiveness to insulin, we examined the effect of insulin infusion on glycogen metabolism in the rat heart 1 wk after transplantation into a nonworking heterotopic infrarenal position. Nonworking heterografts had higher basal glycogen concentrations than did in situ working hearts of the same animals (29.9 +/- 2.7 vs. 23.3 +/- 0.8 mumol/g; P < 0.05), and a smaller fraction of their glycogen synthase enzyme activity was in the physiologically active glycogen synthase I form (8 +/- 2 vs. 22 +/- 3%; P < 0.02). During a 25-min infusion of insulin (1 U/min) and glucose (30 mg.kg-1.min-1), the fractional glycogen synthase I activity of heterografts remained lower than that of in situ hearts (29 +/- 5 vs. 56 +/- 7%; P < 0.02) and heterografts synthesized glycogen more slowly (0.126 +/- 0.07 vs. 0.352 +/- 0.06 mumol.g-1.min-1; P < 0.02). These effects could be duplicated by a 24-h fast, which similarly increased myocardial glycogen concentration (to 32.9 +/- 5.6 mumol/g). These observations suggest that the performance of repetitive contractile work is necessary to maintain the myocardium maximally responsive to insulin. Mechanical unloading increases myocardial glycogen concentration, thereby reducing the magnitude of insulin's stimulation of glycogen synthase and consequently the rate of incorporation of circulating glucose into glycogen.