Mathematical models of myosin heterodimer formation in the rat heart during thyroid hormone alterations.

To characterize the mechanisms involved in the formation of the myosin heavy chain (MHC) heterodimer V2 (alpha beta-MHC) and the homodimers V3 (beta beta-MHC) and V1 (alpha alpha-MHC), 82 5-week-old normotensive rats with homogeneous V1 were made hypothyroid with propylthiouracil (0.8%, drinking water), and the proportion of V2, V3, and V1 was determined by pyrophosphate gel electrophoresis in multicellular specimens of the left and right ventricles. After the switch from alpha-MHC to beta-MHC, the beta-MHC occurred initially in the form of the heterodimer. After 4 and 6 days, V2 was greater (p less than 0.05) than V3. At day 8, V2 was smaller than V3, and at day 10, V2 was not statistically different from V3. From day 12 onward, V2 was smaller than V3. After 21 days, the propylthiouracil treatment was stopped, and the remaining 34 hypothyroid rats were injected with a daily dose of thyroxine (average, 0.1 mg/kg body wt), resulting in a switch from beta-MHC to alpha-MHC. After 1 day, V2 still was greater than V1; however, already from day 3 onward, V2 was smaller than V1. This characteristic but unexplained heterodimeric and homodimeric organization of the thick filament was analyzed by mathematical models involving probability calculations. Two principally different models were established that assume either the exchange of MHC dimers or of single MHC in the thick filament. The parameters of the models were estimated by minimization routines using the squared discrepancies between the experimental and predicted isoenzyme populations. Based on goodness of fit and crucial model parameters, we concluded that the characteristic organization of the thick filament can be accounted for by an exchange involving predominantly MHC dimers and not single MHC. The fact that V2 was lower than expected if formation of heterodimers and homodimers were random was attributed to the preferred homodimerization of 35% of the newly synthesized MHC.